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Understanding the IL-23-IL-17 immune pathway
Abstract
Interleukin (IL)-23 is a heterodimeric cytokine closely related to IL-12. Yet, despite a strong structural relationship that includes a shared p40 subunit, this does not translate into functional similarity. In fact, the opposite is true, in that these two cytokines appear to have profoundly different roles in regulating host immune responses. It is now clear that IL-23 has key roles in autoimmune destruction in experimental allergic encephalomyelitis, collagen-induced arthritis and inflammatory bowel disease. IL-23 drives the development of autoreactive IL-17-producing T cells and promotes chronic inflammation dominated by IL-17, IL-6, IL-8 and tumor necrosis factor as well as neutrophils and monocytes. It is unlikely that IL-23 and its downstream effects evolved just to cause autoimmunity, but its real benefit to the host and the lineage relationship between IL-17-producing cells and T helper 1 cells remain unclear. By comparing the pathophysiological function of IL-12 and IL-23 in the context of host defense and autoimmune inflammation, we are beginning to understand the novel IL-23-IL-17 immune pathway.
... Para su diferenciación, las células Th1 necesitan la presencia de estímulos que favorezcan la producción de IL-12 por parte de las células presentadoras de antígeno (APC), como los organismos intracelulares, lo que lleva a la activación de vías de señalización en las que participan factores de transcripción como STAT1 (del inglés Signal Transducer and Activator of Transcription), STAT4 y t-bet induciendo la producción de Interferón gamma (IFN-γ ) e inhibiendo el desarrollo de una respuesta de tipo Th2. [3][4][5][6][7] Por el contrario, la diferenciación de las células Th2 depende de estímulos que lleven a la producción de IL-4 como los parásitos y los alergenos, que activan los factores de transcripción STAT6, GATA-3 y c-Maf, llevan a la producción del patrón de citoquinas caracterizado por IL-4, IL-5 e IL-13 e inhiben el desarrollo de las células de tipo Th1. [3][4][5][6][7] El anterior paradigma ha sido alterado por hallazgos que sugieren la existencia de un tipo de células T CD4+ efectoras que producen IL-17A que constituye un linaje diferente de los clásicos Th1 y Th2, denominado Th17. ...
... [3][4][5][6][7] Por el contrario, la diferenciación de las células Th2 depende de estímulos que lleven a la producción de IL-4 como los parásitos y los alergenos, que activan los factores de transcripción STAT6, GATA-3 y c-Maf, llevan a la producción del patrón de citoquinas caracterizado por IL-4, IL-5 e IL-13 e inhiben el desarrollo de las células de tipo Th1. [3][4][5][6][7] El anterior paradigma ha sido alterado por hallazgos que sugieren la existencia de un tipo de células T CD4+ efectoras que producen IL-17A que constituye un linaje diferente de los clásicos Th1 y Th2, denominado Th17. 4,8 Se ha evidenciado que este tipo celular no requiere los factores de transcripción que utilizan las células efectoras de los tipos Th1 y Th2, y que los patrones de citoquinas producidos por estos dos tipos celulares impiden el desarrollo de las células T hacia la vía Th17. ...
... 4,8 Se ha evidenciado que este tipo celular no requiere los factores de transcripción que utilizan las células efectoras de los tipos Th1 y Th2, y que los patrones de citoquinas producidos por estos dos tipos celulares impiden el desarrollo de las células T hacia la vía Th17. 4,6 A pesar del desconocimiento de los estímulos que desencadenan de manera preferencial una respuesta de tipo Th17 sobre una de tipo Th1, la diferenciación de las células T vírgenes hacia Th17 es favorecida por la combinación de Interleuquina- del estímulo inicial por el reconocimiento que el complejo TCR (del inglés: T cells receptor) (TCR, CD3, cadenas ζ) hace del péptido antigénico asociado al Complejo Mayor de Histocompatibilidad (MHC), lo cual es un paso primordial en la diferenciación y activación de las células T CD4+ vírgenes. 4,7 No se han identificado totalmente los factores de transcripción requeridos para la diferenciación de las células de tipo Th17. ...
La Interleuquina 17 (IL-17) es una citoquina proinflamatoria con diversas funciones biológicas secretada por varios subtipos de células T activadas. Su receptor se encuentra en los distintos tipos celulares de un amplio rango de tejidos. La IL-17 se ha relacionado con el desarrollo de enfermedades autoinmunes, rechazo de aloinjertos, cáncer, respuestas de hipersensibilidad inmediatas y tardías y control de infecciones, entre ellas la respuesta inmune contra Mycobacterium tuberculosis. Esta revisión pretende abarcar los aspectos hasta ahora elucidados sobre las características, las vías de diferenciación de las células productoras de IL- 17, así como la señalización y funciones de ésta.
... This cytokine considered as a link between nonspecific and specific immunity (11) . IL-23 has many biologic functions like the ability to prompt IL-17 production clarifying its importance in the expression of early immune response against pathogens (12) . Thus IL-23 help in instant neutrophil infiltration to the target organs (13) . ...
... The IL-12-IFN axis is anticipated to become the major route at this time. This outcome is consistent with Th1 response dominating the IL23-IL-17 immunological pathway (12) . When we correlated salivary IL-23 concentration with clinical periodontal parameters, results showed that IL-23 was significantly and negatively correlated. ...
... A su vez, IL-18 e IL-23 incrementan la producción de IFN-γ por los LT activados. 3,[29][30][31][32] TNF-α: esta citoquina proinflamatoria merece especial atención en la psoriasis debido a que su sobreproducción por diferentes tipos de células como macrófagos, monocitos, neutrófilos, mastocitos, células NK, LT activados, células de Langerhans, células dendríticas dérmicas, queratinocitos y células endoteliales, lleva a la activación de la inmunidad innata y de la adaptativa, que conduce a inflamación crónica, daño tisular y proliferación de los queratinocitos. 3,28 El TNF-α induce la activación de las células blanco y la translocación al núcleo del factor de trascripción NF-κB, lo cual a su vez induce la transcripción de TNF-α, GM-CSF, óxido nítrico-sintetasa, ciclo-oxigenasa 2, IL-2 e IL-2R, IL-6, la molécula de adhesión intercelular 1 (ICAM-1, Intercellular adhesion molecule-1), la molécula de adhesión celular vascular 1 (VCAM-1, Vascular cell adhesion molecule-1), la selectina E y la cadena β del TCR; estos efectos se traducen en incremento de la adhesión, migración y proliferación de linfocitos y, al mismo tiempo, contribuyen a la respuesta hiperproliferativa de los queratinocitos. ...
... A diferencia de la piel sana, en biopsias de lesiones psoriáticas se puede detectar ARNm de IL-17, lo que indica que esta interleuquina puede amplificar y mantener la inflamación en la psoriasis. 30,31,33 Quimioquinas Las quimioquinas participan en el reclutamiento de células a la placa psoriática y en la liberación local de citoquinas y factores de crecimiento. 4,32 De estas sustancias, las que participan en la inmunopatogénesis de la psoriasis incluyen CCL17, CXCL9 (monoquina inducida por interferón γ), CXCL10, CCL22, CCL5, CCL27 (quimioquina atrayente de la célula T cutánea), CCL20 (proteína inflamatoria del macrófago), CCL19 y CXCL8 (quimioquina atrayente del neutrófilo). ...
La psoriasis es una de las enfermedades cutáneas más frecuentes pues afecta al 2-3% de la población mundial. Es autoinmune, específica de órgano, crónica y recurrente, desencadenada por factores externos en individuos con predisposición genética. En su inmunopatogénesis se ha descrito una falla en la regulación de la respuesta inmune frente a antígenos aún no bien identificados. Tiene diversas presentaciones clínicas e influye desfavorablemente en la calidad de vida de los pacientes. La comprensión de sus fundamentos inmunopatogénicos ha permitido poner en práctica nuevas estrategias de tratamiento como la terapia biológica. En este artículo se revisan los aspectos fundamentales de la inmunopatogénesis de la psoriasis y sus características epidemiológicas, clínicas e histopatológicas, así como las varias opciones terapéuticas.
... IL-23 is a heterodimeric pro-inflammatory cytokine secreted by dendritic cells and macrophages that belongs to the IL-12 family (McKenzie et al., 2006). It is pro-inflammatory and can stimulate the differentiation and proliferation of downstream effectors such as Th17 cells and is expressed in a variety of diseases, such as tumors (Yan et al., 2018), periodontal disease (Bunte and Beikler, 2019), ocular diseases (Cui et al., 2022), and auto immune diseases, among others. ...
... IL-23 is mainly produced by dendritic cells and macrophages (McKenzie et al., 2006), but non-immune cells such as keratinocytes and synoviocytes can as well secrete it. There are also some immune receptors that enhance the production of IL-23, e.g., Gram-positive bacteria release peptidoglycan, which binds to the toll-like receptor (TLR) 4 (Re and Strominger, 2001) and Gram-negative bacteria produce lipopolysaccharide (LPS), which binds to the TLR3 receptor (Smits et al., 2004), which can effectively induce IL-23 secretion. ...
IL-23 is a heterodimeric pro-inflammatory cytokine secreted by dendritic cells and macrophages that belongs to the IL-12 family. It has pro-inflammatory effects and is a key cytokine and upstream regulatory cytokine involved in protective immune responses, stimulating the differentiation and proliferation of downstream effectors such as Th17 cells. It is expressed in various autoimmune diseases such as psoriasis, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA). The IL-23/TH17 axis formed by IL-23 and TH17 has been confirmed to participate in autoimmune diseases pathogenesis. IL-23R is the receptor for IL-23 and plays an activating role. Targeting IL-23 is currently the main strategy for the treatment of various autoimmune diseases. In this review we summarized the mechanism of action and clinical application potential of IL-23 in autoimmune diseases by summarizing the latest research results and reviewing the literature, which would help to further understand IL-23 and provide a theoretical basis for future clinical targeting and drug development.
... IL-23, a member of the IL-12 family of cytokines, consists of two subunits, IL-12p40, which it shares with IL-12, and IL-23p19, and is secreted by activated dendritic cells and macrophages (Fig. 1) [117,118]. The biological effects exerted by IL-23, including differentiation of naïve T cells to T H 17 cells, proliferation and survival of T H 17 cells, and stimulation of IL-17A release from T H 17 cells, manifest following engagement of IL-23 with its receptor, which also consists of two subunits [IL-12 receptor subunit beta-1 (IL-12Rβ1) and IL-23 receptor (IL-23R)] [119][120][121][122]. Obesity and asthma, independently, increase serum IL-23 in human subjects [123,124], BAL IL-23 is increased to a greater extent in obese as compared to lean mice following exposure to O 3 [100], and inhibition of IL-17A, whose expression can be induced by IL-23, reduces increases in airway responsiveness and BAL KC and neutrophils induced by acute exposure to O 3 [100,125]. ...
Purpose of Review
To discuss the effectiveness of biologics, some of which comprise the newest class of asthma controller medications, and non-biologics in the treatment of asthma co-existing with obesity.
Recent Findings
Our review of recent preliminary and published data from clinical trials revealed that obese asthmatics respond favorably to dupilumab, mepolizumab, omalizumab, and tezepelumab, which are biologics currently indicated as add-on maintenance therapy for severe asthma. Furthermore, clinical trials are ongoing to assess the efficacy of non-biologics in the treatment of obese asthma, including a glucagon-like peptide-1 receptor agonist, a Janus kinase inhibitor, and probiotics.
Summary
Although many biologics presently indicated as add-on maintenance therapy for severe asthma exhibit efficacy in obese asthmatics, other phenotypes of asthma co-existing with obesity may be refractory to these medications. Thus, to improve quality of life and asthma control, it is imperative to identify therapeutic options for all existing phenotypes of obese asthma.
... 1 It is primarily secreted by activated macrophages, dendritic cells, keratinocytes, and other antigenpresenting cells, as well as by T lymphocytes and natural killer cells in peripheral tissues, such as the skin, intestinal mucosa, joints, and lungs. [2][3][4] Although the IL-23/IL-17 axis has a welldocumented protective role against bacterial and fungal infections, 5 its dysregulation can lead to chronic inflammation and autoimmunity, contributing to the development of several diseases, such as psoriasis, psoriatic arthritis, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and others. 5 Because of its significant involvement in various pathogenic conditions, IL-23 has emerged as a promising therapeutic target for chronic inflammatory and autoimmune diseases. ...
Objective
Interleukin‐23 (IL‐23) is a crucial cytokine implicated in chronic inflammation and autoimmunity, associated with various diseases such as psoriasis, psoriatic arthritis, and systemic lupus erythematosus (SLE). This study aimed to create and characterize a transgenic mouse model overexpressing human IL‐23A (TghIL‐23A), providing a valuable tool for investigating the pathogenic role of human IL‐23A and evaluating the efficacy of anti–human IL‐23A therapeutics.
Methods
TghIL‐23A mice were generated via microinjection of CBA × C57BL/6 zygotes with a fragment of the human IL23A gene, flanked by its 5′‐regulatory sequences and the 3′ untranslated region of human β‐globin. The TghIL‐23A pathology was assessed through hematologic and biochemic analyses, cytokine and antinuclear antibody detection, and histopathologic examination of skin and renal tissues. The response to the anti–human IL‐23A therapeutic agent guselkumab was evaluated in groups of eight mixed‐sex mice receiving subcutaneous treatment twice weekly for 10 weeks using clinical, biomarker, and histopathologic readouts.
Results
TghIL‐23A mice exhibited interactions between human IL‐23A and mouse IL‐23/IL‐12p40 and developed a chronic multiorgan autoimmune disease marked by proteinuria, anti–double‐stranded DNA antibodies, severe inflammatory lesions in the skin, and milder phenotypes in the kidneys and lungs. The TghIL‐23A pathologic features exhibited significant similarities to those observed in human patients with SLE, and they were reversed following guselkumab treatment.
Conclusion
We have generated and characterized a novel genetic mouse model of SLE, providing proof‐of‐concept for the etiopathogenic role of human IL‐23A. This new model has a normal life span and integrates several characteristics of the human disease's complexity and chronicity, making it an attractive preclinical tool for studying IL‐23–dependent pathogenic mechanisms and assessing the efficacy of anti–human IL‐23A or modeled disease‐related therapeutics.
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... Patients with varying degrees of severity can now be treated with a variety of topical, systemic, and biologic drugs. Refractory psoriasis is frequently treated with biological therapies, which have been shown to be both safe and efficacious [4,5]. Table 1 shows biological treatments approved in moderate-to-severe chronic plaque psoriasis. ...
Psoriasis is a chronic immune-mediated disease that is linked to an increased risk of cancer. Although numerous studies have explored whether neoplasms are concurrent conditions or are induced by psoriasis, a definitive definition remains elusive. In this study, we conducted a comprehensive narrative literature review to offer practical guidance to oncologists and dermatologists regarding the initiation and discontinuation of biologics for psoriasis. The findings indicate that a customized approach is recommended for each patient, and that a history of malignancies does not constitute an absolute contraindication for biologics. Growing evidence supports the treatment of selected patients, emphasizing a nuanced assessment of benefits and risks. There is a lack of data specifying a safe timeframe to initiate biologics following a neoplasm diagnosis due to influences from cancer-related and patient-specific characteristics impacting prognosis. Some patients may continue anti-psoriasis therapy during cancer treatments. Enhanced comprehension of the biological mechanisms in cancer progression and the immune microenvironment of psoriasis holds promise for refining therapeutic strategies. In conclusion, a personalized treatment approach necessitates collaboration between oncologists and dermatologists, considering factors such as cancer prognosis, psoriasis clinical manifestations, patient characteristics, and preferences when making treatment decisions.
... It is known that neutrophils are important effector cells involved in renal IRI. IL-23 is the initiating factor of the IL-23/IL-17 pathway and plays an important role in the recruitment of neutrophils [50]. To investigate the effect of IL-23 on neutrophils during renal IRI, we constructed a renal IRI model in mice with myeloid-cellspecific IL-23R deficiency (Lyz-IL23R cKO). ...
Neutrophils display heterogeneity and plasticity with different subgroups and immune-regulatory functions under various surrounding conditions. Neutrophils induced by IL-23/IL-18 (referred to N(IL-23+IL-18) neutrophils) have a unique gene-expression profile, with highly expressing IL-17, MHC-II, and costimulatory molecules. The adoptive transfer of N(IL-23+IL-18) neutrophils significantly increased the pathogenesis in a renal ischemia–reperfusion injury mouse model. N(IL-23+IL-18) neutrophils directly and efficiently induced allogeneic T cell proliferation in vitro. N(IL-23+IL-18) neutrophils enhanced the syngeneic T cell response to allogeneic antigens in mixed-lymphocyte reaction assays. The adoptive transfer of the donor or host N(IL-23+IL-18) neutrophils significantly enhanced the antidonor antibody production in an allogeneic-skin-transplanted mouse model, accompanied by increased Tfh cells in the spleens. Therefore, the neutrophil subset induced by IL-23/IL-18 promotes tissue injury and antidonor humoral response in the allogeneic transplantation mouse model.
... Interleukin-17 is an emerging proinflammatory cytokine that has both beneficial and harmful effects. [9,10] .It is a hallmark cytokine of Th17 cells and serves as a link between the innate and adaptive immunity at the mucosal barriers [11]. Emerging as potentially essential participants in the pathophysiology of periodontitis, interleukin-17 (IL-17) and IL-17-producing lymphocytes and innate immune cells are of special interest. ...
Background:Evaluation methods for periodontal disorders are continually being refined to yield more precise, reliable, and time-efficient findings. Radiographic reports and clinical assessments of periodontal tissues, which served as the basis for earlier trends, were used to identify disorders affecting the tooth-supporting structures. As traditional approaches have become more apparent gradually over time, new methods emerged, some of which have been empirically validated. One example is the detection and measurement of biomarkers in bodily fluids. One of the most pressing issues in periodontal field nowadays is the search for an idealized periodontal diagnostic/prognostic biomarker that can both identify diseased areas and track the therapeutic success of periodontal treatment. Both IL-17 and IL-10 have shown connection to periodontitis that could encourage using them as diagnostic tools. Objective: To provide a review of the role and association of the above biomarkers to periodontitis. Patients and Methods: A systematic research of Google scholar, Scopus, PubMed Central, research gate was conducted using keywords such as diagnosis, periodontitis, IL-17, IL-10, biomarkers, Saliva and gingival crevicular fluid (GCF). Results: out of 58 records which resulted from the initial search only 14 were included which used roles, associations, and diagnosis as their outcomes. Conclusion: Evidence from the selected records suggests that the above stated biomarkers might be able to discriminate periodontitis from health, monitoring disease progression and post treatment outcome, but actual clinical application needs much further research. Keywords: periodontitis, Diagnosis, IL-17, IL-10
... Interleukin-17 is an emerging proinflammatory cytokine that has both beneficial and harmful effects. [9,10] .It is a hallmark cytokine of Th17 cells and serves as a link between the innate and adaptive immunity at the mucosal barriers [11]. Emerging as potentially essential participants in the pathophysiology of periodontitis, interleukin-17 (IL-17) and IL-17-producing lymphocytes and innate immune cells are of special interest. ...
Background:Evaluation methods for periodontal disorders are continually being refined to yield more precise, reliable, and time-efficient findings. Radiographic reports and clinical assessments of periodontal tissues, which served as the basis for earlier trends, were used to identify disorders affecting the tooth-supporting structures. As traditional approaches have become more apparent gradually over time, new methods emerged, some of which have been empirically validated. One example is the detection and measurement of biomarkers in bodily fluids. One of the most pressing issues in periodontal field nowadays is the search for an idealized periodontal diagnostic/prognostic biomarker that can both identify diseased areas and track the therapeutic success of periodontal treatment. Both IL-17 and IL-10 have shown connection to periodontitis that could encourage using them as diagnostic tools. Objective: To provide a review of the role and association of the above biomarkers to periodontitis. Patients and Methods: A systematic research of Google scholar, Scopus, PubMed Central, research gate was conducted using keywords such as diagnosis, periodontitis, IL-17, IL-10, biomarkers, Saliva and gingival crevicular fluid (GCF). Results: out of 58 records which resulted from the initial search only 14 were included which used roles, associations, and diagnosis as their outcomes. Conclusion: Evidence from the selected records suggests that the above stated biomarkers might be able to discriminate periodontitis from health, monitoring disease progression and post treatment outcome, but actual clinical application needs much further research.
... IL-23 is a dendritic cells and macrophage derived cytokine shown to promote skin carcinogenesis [12] and renal cell carcinoma [13]. IL-23p19 is the specific subunit of IL-23 that functions in immune-modulation by positively regulating TH17 and other IL-17-producing cells [14]. ...
Inflammation and obesity are two major factors that promote Colorectal cancer (CRC). Our recent data suggests that interleukin (IL)-23, is significantly elevated in CRC tumors and correlates with patient obesity, tumor grade and survival. Thus, we hypothesize that obesity and CRC may be linked via inflammation and IL-23 may be a potential target for intervention in high-risk patients. TCGA dataset and patient sera were evaluated for IL-23A levels. IL-23A [IL-23 p19−/−] knockout (KO) mice were crossed to Apcmin/+ mice and progeny were fed low-fat or high-fat diets. At termination intestines were evaluated for tumorigenesis. Tumors, serum, and fecal contents were analyzed for protein biomarkers, cytokines, and microbiome profile respectively. IL-23A levels are elevated in the sera of patients with obesity and colon tumors. Genetic ablation of IL-23A significantly suppressed colonic tumor multiplicity (76–96 %) and incidence (72–95 %) in male and female mice. Similarly, small-intestinal tumor multiplicity and size were also significantly reduced in IL-23A KO mice. IL-23A knockdown in Apcmin/+ mice fed high-fat diet, also resulted in significant suppression of colonic (50–58 %) and SI (41–48 %) tumor multiplicity. Cytokine profiling showed reduction in several circulating pro-inflammatory cytokines including loss of IL-23A. Biomarker analysis suggested reduced tumor cell proliferation and immune modulation with an increase in tumor-infiltrating CD4+ and CD8+ T-lymphocytes in the IL-23A KO mice compared to controls. Fecal microbiome analysis revealed potentially beneficial changes in the bacterial population profile. In summary, our data indicates a tumor promoting role for IL-23 in CRC including diet-induced obesity. With several IL-23 targeted therapies in clinical trials, there is a great potential for targeting this cytokine for CRC prevention and therapy.
... IL-23 is a dendritic cells and macrophage derived cytokine shown to promote skin carcinogenesis [12] and renal cell carcinoma [13]. IL-23p19 is the specific subunit of IL-23 that functions in immune-modulation by positively regulating TH17 and other IL-17-producing cells [14]. ...
Inflammation and obesity are two major factors that promote Colorectal cancer (CRC). Our recent data suggests that interleukin (IL)-23, is significantly elevated in CRC tumors and correlates with patient obesity, tumor grade and survival. Thus, we hypothesize that obesity and CRC may be linked via inflammation and IL-23 may be a potential target for intervention in high-risk patients. TCGA dataset and patient sera were evaluated for IL-23A levels. IL-23A [IL-23 p19−/−] knockout (KO) mice were crossed to Apcmin/+ mice and progeny were fed low-fat or high-fat diets. At termination intestines were evaluated for tumorigenesis. Tumors, serum, and fecal contents were analyzed for protein biomarkers, cytokines, and microbiome profile respectively. IL-23A levels are elevated in the sera of patients with obesity and colon tumors. Genetic ablation of IL-23A significantly suppressed colonic tumor multiplicity (76–96 %) and incidence (72–95 %) in male and female mice. Similarly, small-intestinal tumor multiplicity and size were also significantly reduced in IL-23A KO mice. IL-23A knockdown in Apcmin/+ mice fed high-fat diet, also resulted in significant suppression of colonic (50–58 %) and SI (41–48 %) tumor multiplicity. Cytokine profiling showed reduction in several circulating pro-inflammatory cytokines including loss of IL-23A. Biomarker analysis suggested reduced tumor cell proliferation and immune modulation with an increase in tumor-infiltrating CD4+ and CD8+ T-lymphocytes in the IL-23A KO mice compared to controls. Fecal microbiome analysis revealed potentially beneficial changes in the bacterial population profile. In summary, our data indicates a tumor promoting role for IL-23 in CRC including diet-induced obesity. With several IL-23 targeted therapies in clinical trials, there is a great potential for targeting this cytokine for CRC prevention and therapy.
... Interestingly, it is also secreted by non-immune cells, such as keratinocytes, synoviocytes, and salivary gland epithelial cells [17][18][19]. The IL-23 signaling pathway occurs through a link with its receptor. ...
Interleukin (IL)-23 is a central pro-inflammatory cytokine with a broad range of effects on immune responses. IL-23 is pathologically linked to the induction of the production of the pro-inflammatory cytokines IL-17 and IL-22, which stimulate the differentiation and proliferation of T helper type 17 (Th17) cells. Recent discoveries suggest a potential pro-fibrotic role for IL-23 in the development of chronic inflammatory autoimmune diseases characterized by intense fibrosis. In this review, we summarized the biological features of IL-23 and gathered recent research on the role of IL-23 in fibrotic autoimmune conditions, which could provide a theoretical basis for clinical targeting and drug development.
... Interestingly, it is also secreted by non-immune cells such as keratinocytes, synoviocytes, and salivary gland epithelial cells [17][18][19]. The IL-23 signaling pathway occurs through a link with its receptor. ...
Interleukin (IL)-23 is a central proinflammatory cytokine with a broad range of effects on immune responses. The pathological consequences of excessive IL-23 signaling have been linked to its ability to promote the production of inflammatory mediators such as IL-17, IL-22 by stimulating the differentiation and proliferation of T helper type 17 (Th17 cells). Emerging evidence suggests a potential pro-fibrotic role for IL-23 in the development of chronic inflammatory autoimmune diseases characterized by intense fibrosis. In this review, we summarized the biological features of IL-23 and gathered recent research on the role of IL-23 in fibrotic autoimmune conditions, which could provide a theoretical basis for clinical targeting and drug development.
... IL-23, a defender against extracellular bacteria, is part of IL-12 family and is produced by dendritic cells and macrophages in peripheral tissues: skin, lungs and intestinal mucosa [7,8]. IL-23 is a heterodimeric cytokine composed of p19 and p40 (shared with IL-12) polypeptidic chains [9]. ...
Background:
interleukin 23 (IL-23) is an important factor involved in the survival and proliferation of T helper 17 cells (Th17), known for their implication in multiple sclerosis (MS). By contrast, IL-27 regulates and modulates the function of T lymphocytes, in particular as a suppressor of Th17 differentiation. The aims of the study were i) to test the association of cytokines with the clinical and genetic characteristics in each of the multiple sclerosis groups (CIS - clinically isolated syndrome, RRMS - relapsing-remitting MS and SPMS - Secondary progressive MS) and ii) to evaluate the association between serum levels of IL-23 and IL-27 with T4730C (IL-27), A964G (IL-27) and R381Q (IL-23) gene polymorphisms in RRMS patients.
Methods:
Blood samples were obtained from 82 patients diagnosed with MS under treatment with glatiramer acetate (GA), interferon beta (IFN) 1 A and 1 B. IL-23 and IL-27 serum concentrations were measured by enzyme-linked immunosorbant assay (ELISA). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used in order to determine the genotypes for R381Q (IL-23) polymorphisms, T4730C (IL-27) and A964G (IL-27).
Results:
Patients with SPMS, RRMS and CIS respectively differed significantly regarding age distribution (p = 0.003) but the studied MS groups were similar regarding age at disease onset (p = 0.528) and treatment type (p = 0.479). A significant increase of mean serum IL-27 was noticed in cases with early onset (age at disease onset <28 years) of RRMS (mean difference: 4.2 pg/ml, 95% CI: 0.8-5.3 pg/ml), compared to cases with later onset of RRMS (age at disease onset ≥28 years). RRMS patients with wild GG genotype of R381Q (IL-23) showed a significant increase of mean serum IL-23 than patients with variant AG genotype (mean difference: 115.1 pg/ml, 95% CI: 8.6-221.6 pg/ml). A trend for a higher increase in means of serum IL-23 (p = 0.086) was observed in RRMS patients carriers of AA genotype of A964G (IL-27) polymorphism in comparison with patients with AG or GG genotypes. We found no significant monotonic correlation of IL-27, IL-23 serum levels with age at disease onset (years) and duration of disease (p > 0.05) in the CIS and SPMS group respectively but a significant correlation between IL-23 and the duration of disease-modifying treatment was noticed only in the SPMS group.
Conclusions:
The results of the current study suggest an association between IL-23 levels and the R381Q gene polymorphism and also a relationship between IL-27 serum levels and early age at disease onset in RRMS patients.
... This cytokine is generally known to act as a proinflammatory and is engaged in Th17 cell stabilization and differentiation via acting on memory T-lymphocytes (16). Moreover, it contributes to activation of memory T lymphocytes and recruiting IL-17 mediated neutrophils [17]. The enzyme creatine kinase (CK) is expressed by different tissues and catalyzes the reversible transfer of high-energy phosphate bond from adenosine triphosphate (ATP) to creatine, and it is a dimer composed of two subunits that are either B (Brain) or M (Muscle). ...
Acute coronary syndrome (ACS) is considered a common cardiovascular disease, in which there is a blood supply reduction to the myocardium, mostly due to atherosclerosis in the coronary arteries. the present study was designed to detect serum markers in Acute coronary syndrome patients infected with COVID-19 in Baghdad Governorate, by evaluating the level of Interleukin-23(IL-23) and level of creatine kinase isoenzyme (CK-MB). Methods: A total of one hundred fifty participants were enrolled in the current study divided into three groups 50 patients with ACS and 50 ACS with COVID-19 patients, while 50 participants as apparently healthy controls. age and sex-matched as healthy controls were involved in the present study. The serum IL-23 and CK-MB levels were measured using an ELISA technique. Serum concentrations of IL-23 and CK-MB were significantly higher in ACS patients and ACS with COVID-19 patients compared to healthy controls (P≤0.01) also there was a highly significant difference at (P≥ 0.01) between ACS patients and ACS with COVID-19 patients. IL- 23 can be considered a biomarker for ACS patients and ACS with COVID-19 patients.
... The transcriptome results showed that the DEGs regulated by Se deficiency were mainly enriched in the stress resistance and organ development biological processes such as immune and defense response, muscle organ development, connective tissue and striated muscle tissue development. The KEGG analysis suggested that the Se deficiency regulated the lipid metabolism related to signal transduction, including sphingolipid metabolism (Merrill et al., 2001), signal transduction and immune function-related pathways including IL-17 signaling pathway (McKenzie et al., 2006), NOD-like receptor signaling pathway (Lamkanfi and Kanneganti, 2012), and Hippo signaling pathway , to produce heart injury. Similar reports have been made in previous studies (Yang et al., 2018;Zhao et al., 2021). ...
Broiler chicks are fast-growing and susceptible to dietary selenium (Se) deficiency. This study sought to reveal the underlying mechanisms of how Se deficiency induces key organ dysfunctions in broilers. Day-old male chicks (n=6 cages/diet, 6 chicks/cage) were fed with a Se-deficient diet (Se-Def, 0.047 mg Se/kg) or the Se-Def+0.3 mg Se/kg (Control, 0.345 mg Se/kg) for 6 weeks. The serum, liver, pancreas, spleen, heart, and pectoral muscle of the broilers were collected at week 6 to assay for Se concentration, histopathology, serum metabolome, and tissue transcriptome. Compared with the Control group, Se deficiency induced growth retardation and histopathological lesions and reduced Se concentration in the five organs. Integrated transcriptomics and metabolomics analysis revealed that dysregulation of immune and redox homeostasis related biological processes and pathways contributed to Se deficiency-induced multiple tissue damage in the broilers. Meanwhile, four metabolites in the serum, daidzein, epinephrine, L-aspartic acid and 5-hydroxyindoleacetic acid, interacted with differentially expressed genes with antioxidative effects and immunity among all the five organs, which contributed to the metabolic diseases induced by Se deficiency. Overall, this study systematically elucidated the underlying molecular mechanisms in the pathogenesis of Se deficiency-related diseases, which provides a better understanding of the significance of Se-mediated heath in animals.
... Moreover, it has been shown that the increase in TGF-levels may predict a worse prognosis in metastatic cancer patients [10], whereas it has appeared to express a control of disease in the autoimmune pathologies [11]. TGFbeta alone would inhibit IL-17 secretion, whereas TGF-beta in association with IL-6 may promote TH17 cell differentiation, with a consequent enhanced IL-17 production [12]. Then, IL-6 levels, which are increased in inflammatory conditions, would constitute the main factor responsible to pilot the effect of TGF-beta on IL-17 secretion in an inhibitory, or in a stimulatory way. ...
... IL-23 has been implicated in other chronic inflammatory conditions, such as intestinal Crohn's disease, and closely associated with the influx of neutrophils in acute infections [15]. This, in turn, induces expression of pro-inflammatory factors like IL-17A, sustaining neutrophil recruitment and long-term maintenance of inflammation at the site of chronic bacterial infection [16]. IL-23 upregulates IL-17A expression through signal transducer and activator of transcription 3 (STAT3)-retinoid related orphan receptor-γ T (RORγT) [17]. ...
Objective:
Peri-implantitis, caused by an inflammatory response to pathogens, is the leading cause of dental implant failure. Poor soft tissue healing surrounding implants - caused by inadequate surface properties - leads to infection, inflammation, and dysregulated keratinocyte and macrophage function. One activated inflammatory response, active around peri-implantitis compared to healthy sites, is the IL-23/IL-17A cytokine axis. Implant surfaces can be synthesized with peptide nanocoatings to present immunomodulatory motifs to target peri-implant keratinocytes to control macrophage polarization and regulate inflammatory axises toward enhancing soft tissue healing.
Methods:
We synthesized an IL-23 receptor (IL-23R) noncompetitive antagonist peptide nanocoating using silanization and evaluated keratinocyte secretome changes and macrophage polarization (M1-like "pro-inflammatory" vs. M2-like "pro-regenerative").
Results:
IL-23R antagonist peptide nanocoatings were successfully synthesized on titanium, to model dental implant surfaces, and compared to nonfunctional nanocoatings and non-coated titanium. IL-23R antagonist nanocoatings significantly decreased keratinocyte IL-23, and downstream IL-17A, expression compared to controls. This peptide noncompetitive antagonistic function was demonstrated under lipopolysaccharide stimulation. Large scale changes in keratinocyte secretome content, toward a pro-regenerative milieu, were observed from keratinocytes cultured on the IL-23R antagonist nanocoatings compared to controls. Conditioned medium collected from keratinocytes cultured on the IL-23R antagonist nanocoatings polarized macrophages toward a M2-like phenotype, based on increased CD163 and CD206 expression and reduced iNOS expression, compared to controls.
Significance:
Our results support development of IL-23R noncompetitive antagonist nanocoatings to reduce the pro-inflammatory IL-23/17A pathway and augment macrophage polarization toward a pro-regenerative phenotype. Immunomodulatory implant surface engineering may promote soft tissue healing and thereby reduce rates of peri-implantitis.
... Gene expression in patients with gangrenous appendicitis was particularly characterized by increase of gene expression associated with neutrophil and monocyte function. The role of the previously relevantly shown Th17-associated mechanisms in gangrenous appendicitis was particularly demarcated by the highly differential regulation of cytokines and transcription factors of the IL-23/IL-17 pathway: IL-17A, IL-23A, IL-23R, IL-27 and SOCS3 (40,45). ...
One of the most common clinical pictures has become the focus of attention during the COVID-19 pandemic: acute appendicitis with the associated diagnostics and therapy. The aim of the work is to show inconsistencies with regard to epidemiology, pathophysiology and therapy against the background of the pandemic with special attention to the conditions for children and to explain the pathophysiological processes that are likely to underlie the disease based on scientifically plausible models.
... Gene expression in patients with gangrenous appendicitis was particularly characterized by increase of gene expression associated with neutrophil and monocyte function. The role of the previously relevantly shown Th17-associated mechanisms in gangrenous appendicitis was particularly demarcated by the highly differential regulation of cytokines and transcription factors of the IL-23/IL-17 pathway: IL-17A, IL-23A, IL-23R, IL-27 and SOCS3 (40,45). ...
... Interleukin (IL)-23 is a heterodimeric pro-inflammatory cytokine, produced by various immune cells. IL-23 is mainly secreted by activated monocytes, macrophages and dendritic cells found in peripheral tissues such as skin, intestinal mucosa and lungs [1]. It can also be secreted by other cells, including innate lymphoid cells, γδ T lymphocytes and B cells [2,3]. ...
Chronic low-grade inflammation induced by obesity is a central risk factor for the development of metabolic syndrome. High low-density lipoprotein cholesterol (LDL-c) induces inflammation, which is a common denominator in metabolic syndrome. IL-23 plays a significant role in the pathogenesis of meta-inflammatory diseases; however, its relationship with LDL-c remains elusive. In this cross-sectional study, we determined whether the adipose tissue IL-23 expression was associated with other inflammatory mediators in people with increased plasma LDL-c concentrations. Subcutaneous adipose tissue biopsies were collected from 60 people, sub-divided into two groups based on their plasma LDL-c concentrations (<2.9 and ≥2.9 mmol/L). Adipose expression of IL-23 and inflammatory markers were determined using real-time qRT-PCR; plasma concentrations of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-c) and LDL-c were determined using the standard method; and adiponectin levels were measured by enzyme-linked immunosorbent assay (ELISA). Adipose IL-23 transcripts were found to be increased in people with high LDL-c, compared to low LDL-c group (H-LDL-c: 1.63 ± 0.10–Fold; L-LDL-c: 1.27 ± 0.09–Fold; p < 0.01); IL-23 correlated positively with LDL-c (r = 0.471, p < 0.0001). Immunochemistry analysis showed that AT IL-23 protein expression was also elevated in the people with H-LDL-c. IL-23 expression in the high LDL-c group was associated with multiple adipose inflammatory biomarkers (p ≤ 0.05), including macrophage markers (CD11c, CD68, CD86, CD127), TLRs (TLR8, TLR10), IRF3, pro-inflammatory cytokines (TNF-α, IL-12, IL-18), and chemokines (CXCL8, CCL3, CCL5, CCL15, CCL20). Notably, in this cohort, IL-23 expression correlated inversely with plasma adiponectin. In conclusion, adipose IL-23 may be an inflammatory biomarker for disease progression in people with high LDL-c.
... The main secretory cells for IL-23 are activated macrophages and dendritic cells in peripheral tissues like the intestinal mucosa and skin (McKenzie, B. S. et al, 2006). ...
Background: Urinary catheters are considered as one of the complicating factors for urinary tract infections (UTIs). Many factors have an important impact in the development as well as limitation of the inflammation accompanying the infection in urinary tissues In this work, we aimed at evaluating the urine levels of IL23 in patients using indwelling urinary catheters Methods: A total of ninety four patients with long-term Foley catheter usage who have been admitted to three different teaching hospitals in Baghdad-Iraq, during the period extended from September to December2019. Urine samples were collected from them. Isolation and Identification of bacteria were done according to the standard procedures and considerations. Interleukin-23 detection in urine was made using ELISA. Data were entered, checked and analyzed using SPSS version 26 and STATISTICA version 12. Results: Most of the study sample found to have a positive culture for bacteria (66%); of which 22% found to have Klebsiella pneumoniae, 21% have Escherichia coli, 12% Proteus mirabilis and 11% have Providencia stuartii. The mean of urine IL-23 concentrations in positive culture was significantly higher than that of negative one (132.547 ± 66.3644 vs. 55.266 ± 33.3776) respectively. Besides, significant differences were found in the means of urine IL-23 concentrations among different bacterial UTIs forms with mean square differences between groups was 128090.827 and within groups was 3383.801(F: 9.464, df: 4, P: 0.000) Conclusion: Urine IL23 level is likely to be affected by UTI in patients using indwelling urinary catheters.
... Cumulative graph is maintained or plotted as particle size against time to study effect of particle size on drug release [17]. ...
Objective: Formulation and evaluation of clobetasol-17-propionate-loaded carboxymethyl chitosan nanoparticle. Psoriasis is a chronic skin disorder caused due to the autoimmune factors. It has a detrimental psychological and physiological impact on patients due to the emergence of apparent skin. The systemic therapy with anti-psoriatic drugs such corticosteroids, immunosuppressant, and gene suppressors causes severe side effects. As a result, increasing the effectiveness and safety of the aforementioned medicines when applied topically would be extremely useful in avoiding the side effects associated with the systemic route of administration. Methods: Chitosan (CS) has not been widely used in the clinic applications but due to its limited solubility and poor mechanical characteristics. CS, on the other hand, is chemically changed to form carboxymethyl (CMC), which is soluble at both neutral and basic pH. Chemical modifications can also be used to attach different functional groups and control hydrophobic, cationic, and anionic properties. CMC is a promising carrier that might possibly traverse the thick scales of psoriatic skin since it is a penetration enhancer that allows drug diffusion through either the transcellular or paracellular pathways. Comparative study is done using CMC as a polymer and CD as a polymer. Results: CP-loaded CMC nanoparticles show better result results than CP-loaded CD polymer. Conclusion: Clobetasol-17-propionate-loaded carboxymethyl chitosan nanoparticle shows better results with improved solubility.
... Il-10 binds to the corresponding receptor and initiates transcription of target genes by activating JAK1 and Tyk2, which subsequently leads to phosphorylation of STAT3 (21, 22). Clinically relevant studies have demonstrated that NSCLC patients expressing high levels of IL-10 have poor prognosis (23,24).However, it has also been reported that insufficient expression of IL-10 in tumors is a negative prognostic factor for early-stage NSCLC (21, 25,26). These inconsistent studies on IL-10 suggest that the cellular source of IL-10 and the effects of IL-10 on different cell types are what determine the ultimate role of IL-10 in cancer (27). ...
Background
At present, immunotherapy has become an important treatment for lung cancer. With the widespread use of immune checkpoint inhibitors (ICIs), we must be strict with the emergence of immune related adverse events (irAEs). There are also some patients who do not respond to immunotherapy. However, there was no biomarkers to predict the safety and efficacy of immunotherapy. The selection of immunotherapy beneficiaries contributes to improving the efficacy and safety of lung cancer treatment.
Method
The electronic medical records of 221 lung cancer patients with complete clinical data who received immunotherapy from the First Affiliated Hospital of Xi ‘an Jiaotong University from November 2020 to October 2021 were collected and followed up. IBM SPSS Statistic 26.0 and R 4.1.2 software were used for statistical analysis and mapping.
Results
1. A total of 221 lung cancer patients receiving immunotherapy were included in the study. Higher baseline levels of IL-1β (7.88 vs 16.16pg/mL, P=0.041) and IL-2 (1.28 vs 2.48pg/mL, P=0.001) were significantly associated with irAEs. Higher levels of IL-5 (2.64 vs 5.68pg/mL, P=0.013), IFN-α (1.70 vs 3.56pg/mL, P=0.004) and IFN-γ (6.14 vs 21.31pg/mL, P=0.022) after the first cycle therapy were associated with irAEs. There was no statistical significance between cytokines and irAEs after the second cycle therapy. Higher IL-5 levels in peripheral blood (9.50 vs 3.57pg/mL, P=0.032) were associated with the occurrence of irAEs after the third cycle therapy. 2.The efficacy of immunotherapy was assessed in 142 lung cancer patients. There was no statistical significance between baseline cytokine levels and clinical benefit. After the first cycle therapy, the level of serum cytokines had no statistical significance with the occurrence of immunotherapy clinical benefit. Lower serum levels of IL-10 (2.66 vs 1.26pg/mL, P=0.016) and IL-17 (8.47 vs 2.81pg/mL, P=0.015) were associated with clinical benefit after the second cycle therapy. Lower serum levels of IL-6 (10.19 vs 41.07pg/mL, P=0.013) and IL-8 (8.01 vs 17.22pg/mL, P=0.039) were associated with clinical benefit of immunotherapy after the third cycle therapy.
Conclusion
1. Baseline IL-1β and IL-2 levels in peripheral blood were associated with the occurrence of irAEs in lung cancer patients. The levels of IL-5, IFN-α and IFN-γ during treatment were associated with irAEs. 2. Baseline cytokine levels in peripheral blood were not associated with immunotherapy efficacy. The levels of IL-6, IL-8, IL-10, and IL-17 levels during treatment were associated with immunotherapy efficacy.
... [31][32][33][34] We postulate that tildrakizumab may also have a secondary effect on biofilm colonies in PG. S. aureus may trigger Th1/Th17 responses, 35,36 which are associated with biofilm formation and could exacerbate chronic infection. 36,37 As IL-23 is required for the maintenance of Th17 cells, 36,38 inhibition of IL-23 by tildrakizumab may additionally suppress these inflammatory host responses and hinder biofilm development in PG. ...
Elevated levels of inflammatory mediators—including the interleukin IL-23—are implicated in the pathogenesis of pyoderma gangrenosum (PG), an autoinflammatory neutrophilic dermatosis characterized by rapidly enlarging, suppurative ulcers and cribriform scarring. Here, we present the first case report of significant response of isolated ulcerative PG with tildrakizumab, a biologic agent directed against the p19 subunit of IL-23, in an elderly woman with extensive treatment-refractory PG on her left leg. Tildrakizumab (100 mg subcutaneously at weeks 0 and 4, then every 8 weeks, and eventually increased in frequency to every 6 weeks), combined with acetic acid soaks each morning and chemical debridement every evening with 3% hydrogen peroxide, resulted in progressive decrease in ulcer size and depth, re-epithelialization, and recovery of sensory perception. This report describes the dramatic clinical response of ulcerative PG on the leg with tildrakizumab.
... 6 IL-17 is produced by differentiation of Th17. 9 IL-17 produced by the differentiation of Th17 induced by IL-23. IL-23 is a cytokine produced by mononuclear cells. ...
Background: Acne vulgaris is a chronic inflammatory disease in the pilosebaceous gland of the skin which can cause depression and anxiety. IL-23 is a cytokine that is involved in autoimmune diseases, including acne vulgaris. IL-23 affects the differentiation process of Th17 which further produces IL-17, an important component in the pathogenesis of acne vulgaris. IL-17 plays a significant role in the grade of skin damage caused by the inflammation process.Objective: To find out differences in IL-23 serum levels and the grade of AV severity in women.Methods: An observational study with a cross-sectional design approach conducted from June until October 2020 in 15 women with AV aged 15-25 years old, not consuming anti-inflammatory drugs, antibiotics, retinoid group of drugs and free from other inflammatory diseases. Subjects were divided into three groups based on the AV severity grade: specifically mild (n=5), moderate (n=5) and severe (n=5). Subjects had venous blood taken for IL-23 serum content by the ELISA method. Data on IL-23 serum content in the three groups were tested using the One-Way ANOVA method to determine the differenceResults: Average age from the 3 groups was 21 (17-23 ) years old. The results showed that there is no significant difference in IL-23 rate from the 3 groups of AV severities (p=0,490).Conclusion: : There is no significant difference of IP-23 rate between the 3 groups of AV severites in women.
... The developing embryo modulates the maternal immune system and promotes maternal tolerance to the embryo during the peri-implantation period [43]. T helper 17 (Th17) cells produce IL-17 which recruits neutrophils via granulocyte colony-stimulating factor and IL-8 [44]. Th17 cells are known to regulate the inflammatory process in the endometrium required for the establishment and maintenance of pregnancy [45]. ...
Background
Maternal recognition is the crucial step for establishing pregnancy in cattle. This study aims to identify endometrial genes and biological pathways involved in the maternal recognition of pregnancy. Caruncular endometrial tissues were collected from Day 15–17 of gestation (pregnant), non-pregnant (absence of conceptus), and cyclic (non-bred) heifers.
Results
Total RNAs were isolated from the caruncular endometrial tissues of pregnant, non-pregnant, and cyclic heifers, and were subjected to high-throughput RNA-sequencing. The genes with at least two-fold change and Benjamini and Hochberg p -value ≤ 0.05 were considered differentially expressed genes and further confirmed with quantitative real-time PCR. A total of 107 genes (pregnant vs cyclic) and 98 genes (pregnant vs non-pregnant) were differentially expressed in the pregnant endometrium. The most highly up-regulated genes in the pregnant endometrium were MRS2 , CST6 , FOS , VLDLR , ISG15, IFI6, MX2 , C15H11ORF34 , EIF3M , PRSS22 , MS4A8 , and TINAGL1 . Interferon signaling, immune response, nutrient transporter, synthesis, and secretion of proteins are crucial pathways during the maternal recognition of pregnancy.
Conclusions
The study demonstrated that the presence of conceptus at Day 15–17 of gestation affects the endometrial gene expression related to endometrial remodeling, immune response, nutrients and ion transporters, and relevant signaling pathways in the caruncular region of bovine endometrium during the maternal recognition of pregnancy.
... It has been shown that low levels of IL-23 may lead to deficient immunity in the mucosal 489 barrier, and an enhanced risk of respiratory infections 168 . A study found that psoriasis patients 490 treated with biologics had a higher risk for SARS-CoV-2 infection and hospital admission. ...
The Coronavirus Disease 2019 (COVID-19) pandemic constitutes a global health emergency. Currently, there are no completely effective therapeutic medications for the management of this outbreak. The cytokine storm is a hyperinflammatory medical condition due to excessive and uncontrolled release of pro-inflammatory cytokines in patients suffering from severe COVID-19, leading to the development of acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome (MODS) and even mortality. Understanding the pathophysiology of COVID-19 can be helpful for the treatment of patients. Evidence suggests that the levels of tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1 and IL-6 are dramatically different between mild and severe patients, so they may be important contributors to the cytokine storm. Several serum markers can be a predictor for the cytokine storm. This review discusses the cytokines involved in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, focusing on interferons (IFNs) and ILs, and whether they can be used in COVID-19 treatment. Moreover, we highlight several microRNAs which are involved in these cytokines, and their role in the cytokine storm caused by COVID-19.
... However, as compared to placebo, adverse events are more common. IL-23 is produced by various immune cells in response to microbial products and inflammatory cytokines, and it functions as a link between the innate and adaptive immune systems, driving early local immunity [35]. The unique IL-23-p19 subunit is linked to the shared p40 subunit found in IL-12 to form the structure of IL-23. ...
Background:
Psoriasis is an immune-mediated protracted ailment that perturbs about 100 million people globally. Anti-interleukin (IL)-23 agents have a distinctive status of safety and clinical efficacy. Anti-IL-23 operatives have demonstrated therapeutic prominences in cases of psoriasis in preceding global research. However, arrays of adverse events have been associated with the anti-IL-23 agents in the remedies of psoriasis. This systematic review aimed to assess the adverse developments of anti-IL-23 operatives for patients with psoriasis determined in phase III trials.
Methodology:
The PRISMA guidelines were wielded for this systematic review. The author systematically searched Google Scholar, PubMed, Scopus, and Cochrane databases to diagnosticate appropriate articles on adverse effects of anti-IL-23 agents in patients with psoriasis including the appropriate key terms (Medical Subject Headings).
Results:
A total of 18 studies were encompassed in this cutting-edge systematic review that met the selection criteria. In this review, the most prevailing adverse effect caused by anti-IL-23 agents was nasopharyngitis followed by headache, upper respiratory tract infection, and back pain, which are observed during the treatment with anti-IL-23 agents. The anti-IL-23 operatives, including ustekinumab and guselkumab, were significantly involved in the grade 3 stage of adverse effects for the treatment of psoriasis, whereas the anti-IL-23 agents including briakinumab, tildrakizumab, and risankizumab were significantly involved in the grade 4 stage of adverse effects.
Conclusion:
Targeted IL-23 therapy has expeditiously upsurged to the forefront as the importance of the IL-23 axis has been progressively identified, setting a new benchmark for psoriasis outcomes. Over the last 3 years, ustekinumab, guselkumab, tildrakizumab, and risankizumab have successively come to the market. However, these drugs caused several immunological and nonimmunological side effects, but they are customarily well-tolerated and have orderly safety vignettes.
... The IL-23/IL-17 axis executes body surface pathogen clearance through the prompt recruitment of neutrophils [107], with psoriasis (psoriasiform tissue reactions [108]) being an epitome of such tissue responses. Therefore, one might have expected the results from the omics approach, given that defects in the epidermal structure cause most ichthyosiform dermatoses and can activate the primary immune defense of the skin (so-called "preemptive" immunity [109]) imprinted within the tissue [110][111][112]. ...
Cornification is a specialized mode of the cell-death program, exclusively, and is allowed for terrestrial amniotes. Recent investigations suggest that loricrin (LOR) is an important cornification effector. As the connotation of its name (“lorica” meaning an armor in Latin) suggests, the keratin-associated protein LOR promotes the maturation of the epidermal structure through organizing covalent cross-linkages, endowing the epidermis with the protection against oxidative injuries. By reviewing cornification mechanisms, we seek to classify ichthyosiform dermatoses based on their function, rather than clinical manifestations. We also reviewed recent mechanistic insights into the Kelch-like erythroid cell-derived protein with the cap “n” collar homology-associated protein 1/nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway in skin health and diseases, as LOR and NRF2 coordinate the epidermis-intrinsic xenobiotic metabolism. Finally, we refine the theoretical framework of cross-talking between keratinocytes and epidermal resident leukocytes, dissecting an LOR immunomodulatory function.
... IL 23 is produced by activated macrophages and dendritic cells in many peripheral tissues, such as skin in psoriasis, the intestinal mucosa in inflammatory bowel disease and the joints in rheumatoid arthritis, emphasizing IL 23's critical role in the development of a wide range of autoimmune disorders. [2][3][4].Describing how the immune system is activated by IL 23, activation of T helper 17 (Th17) cells, a unique subpopulation of γδ T cells, subtypes of natural killer T cells, and innate lymphoid cells are the most well-known responses to IL 23 activation. When Th17 cells are stimulated by IL 23 and certain cytokines, they produce interleukin 17A, also known as interleukin 17 (IL 17) [5,6]. ...
... IL-23 combined with TGF-β and IL-6 determines the differentiation of Th17, in which TGF-β plus IL-6 (mainly produced by monocytes/macrophages) act as the differentiation factor and IL-23 acts as the growth and stabilization factor [170]. Rapid IL-23/IL-17 immune response can promote chronic inflammation with cytokines such as IL-17, IL-6, IL-8, and TNF [171]. For example, activated sentinel DCs and macrophages produce IL-23 to trigger the release of IL-17 from tissue-resident T cells and NK cells. ...
Helicobacter pylori is a spiral-shaped gram-negative bacterium. Its infection is mainly transmitted via oral-oral and fecal-oral routes usually during early childhood. It can achieve persistent colonization by manipulating the host immune responses, which also causes mucosal damage and inflammation. H. pylori gastritis is an infectious disease and results in chronic gastritis of different severity in near all patients with infection. It may develop from acute/chronic inflammation, chronic atrophic gastritis, intestinal metaplasia, dysplasia, and intraepithelial neoplasia, eventually to gastric cancer. This review attempts to cover recent studies which provide important insights into how H. pylori causes chronic inflammation and what the characteristic is, which will immunologically explain H. pylori gastritis.
... On the other hand, IL-23 is crucial for the Th17 differentiation and is involved in the production of IL-17A and IL-17F by NK cells. In terms of signalling mechanisms, both IL-12 and IL-23 share similar pathways, such as JAK2, TYK2, STAT1, STAT3, STAT4 and STAT5 [151,152]. ...
Spondyloarthritis (SpA) is a family of chronic inflammatory diseases, being the most prevalent ankylosing spondylitis (AS) and psoriatic arthritis (PsA). These diseases share genetic, clinical and immunological features, such as the implication of human leukocyte antigen (HLA) class I molecule 27 (HLA-B27), the inflammation of peripheral, spine and sacroiliac joints and the presence of extra-articular manifestations (psoriasis, anterior uveitis, enthesitis and inflammatory bowel disease). Monocytes and macrophages are essential cells of the innate immune system and are the first line of defence against external agents. In rheumatic diseases including SpA, the frequency and phenotypic and functional characteristics of both cell types are deregulated and are involved in the pathogenesis of these diseases. In fact, monocytes and macrophages play key roles in the inflammatory processes characteristics of SpA. The aim of this review is analysing the characteristics and functional roles of monocytes and macrophages in these diseases, as well as the impact of different current therapies on these cell types.
... The immunopathogenesis of psoriasis is complex and involves variations in the innate immunologic system (keratinocytes, dendritic cells, histiocytes, neutrocytes, mastocytes, endothelial cells) and acquired (T lymphocytes) [25]. When the cells of the Innate Immunologic System (IIS) are activated, they produce growth factors, cytokines and chemokines that act upon the cells of the Acquired Immunologic System (AIS) and vice-versa [24][25][26][27][28]. ...
Interleukins (ILs) are vital in regulating the immune system, enabling to combat fungal diseases like candidiasis effectively. Their inhibition may cause enhanced susceptibility to infection. IL inhibitors have been employed to control autoimmune diseases and inhibitors of IL-17 and IL-23, for example, have been associated with an elevated risk of Candida infection. Thus, applying IL inhibitors might impact an individual’s susceptibility to Candida infections. Variations in the severity of Candida infections have been observed between individuals with different IL inhibitors, necessitating careful consideration of their specific risk profiles. IL-1 inhibitors (anakinra, canakinumab, and rilonacept), IL-2 inhibitors (daclizumab, and basiliximab), and IL-4 inhibitors (dupilumab) have rarely been associated with Candida infection. In contrast, tocilizumab, an inhibitor of IL-6, has demonstrated an elevated risk in the context of coronavirus disease 2019 (COVID-19) treatment, as evidenced by a 6.9% prevalence of candidemia among patients using the drug. Furthermore, the incidence of Candida infections appeared to be higher in patients exposed to IL-17 inhibitors than in those exposed to IL-23 inhibitors. Therefore, healthcare practitioners must maintain awareness of the risk of candidiasis associated with using of IL inhibitors before prescribing them. Future prospective studies need to exhaustively investigate candidiasis and its associated risk factors in patients receiving IL inhibitors. Implementing enduring surveillance methods is crucial to ensure IL inhibitors safe and efficient utilization of in clinical settings.
Psoriasis is a chronic inflammatory skin condition characterized by Th17 T cell-mediated inflammation. An emerging treatment option for psoriasis is bimekizumab, a humanized monoclonal antibody targeting cytokines IL-17A and IL-17F. Phase I trials evaluating bimekizumab reported strong safety, tolerability, and clinical efficacy with most common treatment emergent adverse events being mild to moderate in nature. Phase II trials evaluated dosing intervals, revealing that higher dosages or more frequent administration of bimekizumab resulted in minimal increases in adverse events. Phase III trials and open label extension studies demonstrated a rapid, sustained clinical response when compared with placebo and active comparators. Bimekizumab shows strong efficacy in the treatment of psoriasis and has potential in the treatment of other Th17-mediated pathologies.
Interleukin 12 (IL-12) is a heterodimer consisting of 2 subunits, p35 and p40, with unique associations and interacting functions with its family members. IL-12 is one of the most important cytokines regulating the immune system response and is integral to adaptive immunity. IL-12 has shown marked therapeutic potential in a variety of tumor types. This review therefore summarizes the characteristics of IL-12 and its application in tumor treatment, focusing on its antitumor effects in colorectal cancer (CRC) and potential radiosensitization mechanisms. We aim to provide a current reference for IL-12 and other potential CRC treatment strategies.
Recently, artificial skin has been widely used to evaluate the biochemical safety and efficacy of certain drugs. Macrophages play a crucial role in the skin immune response by interacting with fibroblasts and keratinocytes. Transcriptional analysis is a cost-effective method to assess the immune response of macrophages in artificial skin. However, high variability in the mRNA levels of inflammatory factors increases the difficulty of evaluating their immunity against biochemicals. In this study, three-dimensional (3D) artificial skin models were identified to be more sensitive to inflammatory transcription levels than two-dimensional (2D) cultures during the interactions of macrophages, fibroblasts, and keratinocytes. Lipopolysaccharides significantly increased the interleukin (IL)-1β and IL-6 levels in 3D fibroblasts/keratinocytes than in 2D culture. They also significantly upregulated IL-1β, IL-6, IL-23, and tumor necrosis factor-α levels in the 3D macrophage/fibroblast/keratinocyte model. In addition, the macrophage-containing 3D skin was evaluated as a promising model for inflammatory transcriptional analysis via in vitro psoriasis studies using imiquimod.
Psoriasis is a chronic inflammatory skin disease that is difficult to treat. Quercetin (QT) is a dietary flavonoid known for its anti-inflammatory effects and safe use in humans. However, the topical application of quercetin for psoriasis treatment presents a significant challenge due to its poor water solubility and low stability in semisolid preparations, where it tends to recrystallize. This work presents a novel liposome-in-gel formulation for the quercetin-based topical treatment of psoriasis. The quercetin-loading liposomes are stabilized by hydroxypropyl-β-cyclodextrin (HPCD), which interacts with phospholipids via hydrogen bonding to form a layer of an HPCD coating on the liposome interface, thus resulting in improved stability. Various analytical techniques, such as FTIR spectroscopy, Raman spectroscopy, and TEM, were used to characterize the molecular coordination patterns between cyclodextrin and liposomes. The results demonstrated that HPCD assisted the liposomes in interfacing with the matrix lipids and keratins of the stratum corneum, thereby enhancing skin permeability and promoting drug penetration and retention in the skin. The in vivo results showed that the topical QT HPCD-liposome-in-gel improved the treatment efficacy of psoriatic plaque compared to free QT. It alleviated the symptoms of skin thickening and downregulated proinflammatory cytokines, including TNF-α, IL-17A, and IL-1β. The results suggested that the HPCD-coordinated liposome-in-gel system could be a stable carrier for topical QT therapy with good potential in psoriasis treatment.
The protection of the blood-brain barrier (BBB) is the key direction to improving subarachnoid hemorrhage (SAH). Therefore, developing appropriate targeted drugs and therapies has become an urgent task for SAH patients. In this study, we investigated the role of dendritic cells (DCs) exosomal miR-3064-5p in repairing the BBB, providing a new basis for treating SAH. We detected the expression of miR-3064-5p in exosomes secreted by DCs (DCs-exo). An SAH rat model was constructed by intravascular perforation and characterized by HE and TUNEL-IF staining. We found that overexpression of miR-3064-5p in SAH rats suppressed iNOS expression and promoted the accumulation of tight junction proteins (Occludin, Claudin-3, ZO-1), whereas knockdown of miR-3064-5p exerted the opposite effect. Dual-LUC assay confirmed that miR-3064-5p could target and inhibit SIRT6. Knockdown of SIRT6 inhibited inflammatory cytokine (IL-6, IL-1β, IFN-γ, and TGF-β1) levels and apoptosis. The results of the co-IP assay showed that SIRT6 interacted with PCSK9, and knockdown of SIRT6 suppressed the expression of PCSK9. Moreover, DCs-exo reduced brain edema, upregulated miR-3064-5p and downregulated SIRT6 and PCSK9 in SAH rats. DCs-exo reduced inflammatory factors and increased tight junction proteins in SAH rats. Overexpression of miR-3064-5p enhanced the protective effect of DCs-exo, while overexpression of SIRT6 partially counteracted the effect. This study confirmed that DCs could secrete miR-3064-5p to ameliorate BBB damage after SAH. Mechanistically, miR-3064-5p alleviated BBB damage by targeting and inhibiting SIRT6/PCSk9 signaling pathway.
Diabetes mellitus type 2 is a disorder of metabolic of multiple etiology characterized by chronic hyperglycemia with disturbance in the metabolism of carbohydrate, lipid and protein. It suggested as a low-grade systemic inflammation disease. One common risk factor that leads to type 2 diabetes mellitus (T2DM) is obesity. IL-23 identified as a central cytokine in autoimmunity and a highly promising treatment target for inflammatory diseases. Herpes simplex virus type 1 (HSV) is associated in females with T2DM. This study aims to investigate the role of IL-23 in diabetic obese and non-diabetic obese women and explore if there is a correlation between this interleukin and HSV-1. Eighty-four females were included in this study. 28 females were diabetic obese, 28 females obese and 28 healthy females' volunteers were taken as control. Biochemical tests, fasting blood glucose (FBS), total cholesterol, and triglyceride (TG) were measured using the colorimetric method by spectrophotometer while IL-23 and HSV measured using the ELISA technique. The results were a highly significant elevation in interleukin-23 level in both obese diabetic patients (58.46± 4.55 ng/ml) and obese nondiabetics (43.86 ±2.05 ng/ml) in comparison with a control group (37.50± 3.29 ng/ml). these results clear the association of raised IL23 with a chronic low-grade inflammation which a function of diabetes and obesity. HSV levels have the same results but both parameters have a very weak correlation in diabetic obese and non-diabetic obese women (r=-.224). We conclude that IL23 have raised levels in obese and to higher levels in diabetic obese women. This elevation failed to correlate with HSV elevation although both diabetes and HSV led to same complication i.e. cardiovascular disease.
Tuberculosis (TB) remains a leading cause of morbidity and mortality worldwide. To date, the mainstay of vaccination involves the use of Mycobacterium bovis bacillus Calmette-Guérin (BCG), a live-attenuated vaccine that confers protection against extrapulmonary disease in infants and children but not against lung disease. Thus, there is an urgent need for novel vaccines. Here, we show that a multicomponent acellular vaccine (TB-MAPS) induces robust antibody responses and long-lived systemic and tissue-resident memory Th1, Th17, and cytotoxic CD4⁺ and CD8⁺ T cells, and promotes trained innate immunity mediated by γδT and NKT cells in mice. When tested in a mouse aerosol infection model, TB-MAPS significantly reduced bacterial loads in the lungs and spleens to the same extent as BCG. When used in conjunction with BCG, TB-MAPS further enhanced BCG-mediated protection, especially in the lungs, further supporting this construct as a promising TB vaccine candidate.
IMPORTANCE Tuberculosis (TB) remains a leading cause of morbidity and mortality worldwide. Here, we evaluate a novel vaccine which induces a broad immune response to Mycobacterium tuberculosis including robust antibody responses and long-lived systemic and tissue-resident memory Th1, Th17, and cytotoxic CD4⁺ and CD8⁺ T cells. When tested in a mouse aerosol infection model, this vaccine significantly reduced bacterial loads in the lungs and spleens to the same extent as BCG. When used in conjunction with BCG, TB-MAPS further enhanced BCG-mediated protection, especially in the lungs, further supporting this construct as a promising TB vaccine candidate.
Background:
Migraine is a type of primary headache caused by changes in the trigeminal system and has been reported to be associated with neurovascular inflammation of cerebral and extracerebral vessels.
Objective:
It is known that inflammation is an important process in the pathogenesis of migraine. It has been shown that the molecules of visinin-like protein 1 (Vilip-1), YKL-40, lipocalin-2 and interleukin (IL)-23 play a role in the inflammatory process. Our aim is to investigate the role of this molecule in the metabolic pathway of migraine disease.
Methods:
Fifty migraine patients with and without aura in the interictal period were included in the study. Vilip-1, YKL-40, lipocalin-2, and IL-23 levels were measured by ELISA method.
Results:
Serum vilip-1, YKL-40, lipocalin-2, and IL-23 levels were found to be significantly higher in migraine patients compared to the control group. We found that this molecule increased significantly in migraine subgroups compared to the control group (p < 0.001). A positive significant correlation was found between vilip-1 level and YKL-40 and lipocalin-2 levels in migraine patients. In addition, a positive correlation was observed between visual analogue scale score, number of days with pain and vilip-1 level (p < 0.01). The results of our study showed that activation of inflammatory mediators may play a role in the pathogenesis of migraine disease. In addition, our study is valuable in that inflammatory molecules are high in the interictal period and these biomarkers have never been analyzed in migraine patients. However, we still believe that larger studies are needed to explain the role of vilip-1, YKL-40, lipocalin-2, and IL-23 in the molecular mechanism of migraine disease.
Background:
Several investigations have disclosed the involvement of the interleukin (IL)-23/IL-17 pathway in rheumatoid arthritis (RA) pathogenesis. Here we investigated the association of single nucleotide polymorphisms (SNPs) in the IL23 receptor (IL23R) gene with RA risk. In addition, the role of these SNPs with the inflammatory state of the patients were determined.
Methods:
In this case-control study, 200 RA cases and 200 healthy subjects were recruited. Using allelic discrimination real-time polymerase chain reaction, both IL23R rs10489629 and rs1004819 SNPs were genotyped. The messenger RNA (mRNA) expression levels of IL-23R, IL-23, and IL-17A were determined in peripheral blood mononuclear cells (PBMCs). The serum levels of IL-23 and IL-17A were also determined.
Results:
The A allele (odds ratio [OR] = 1.52, 95% CI: 1.15-2.01; P = .0030), AA genotype (OR = 2.41, 95% CI: 1.33-4.35; P = .0035), and AG genotype (OR = 2.55, 95% CI: 1.56-4.16, P = .0002) of rs1004819 SNP was significantly associated with increased RA risk. The mRNA expression of IL-17A (fold change = 2.55, P = .00027), IL-23 (fold change = 1.62, P = .0081), and IL-23R (fold change = 1.59, P = .0077) was significantly upregulated in the PBMCs from RA patients compared to that of healthy controls. Serum levels of IL-17A (P = .00019) and IL-23 (P = .00055) was significantly higher in the RA patients compared to the controls. No significant association was detected between patient data and SNPs.
Conclusions:
The IL-23/IL-27 pathway plays a role in RA pathogenesis, but IL23R gene rs1004819 SNP might not be regulating this pathway in RA disease.
Introduction:
Interleukin 23 (IL-23) is a pro-inflammatory cytokine that plays a protective role against bacterial and fungal infections. However, the dysregulation of the IL-23/IL-17 axis provides a solid substrate for the development of various inflammatory diseases, such as psoriatic arthritis (PsA) and ankylosing spondylitis (AS).
Areas covered:
In different clinical trials, several drugs against IL-23 have shown efficacy and safety towards PsA, with excellent results on skin and joint scores. However, the same drugs did not show the same efficacy in AS, suggesting that IL-23 may not be a relevant driver of the pathobiology and clinical symptoms of active axial spondyloarthritis (axSpA).
Expert opinion:
These drugs have shown an excellent efficacy and a good safety profile towards PsA, while in AS the efficacy of the IL-23 blockade is lacking for reasons not yet known. Several hypotheses have been reported, but further studies will be needed for a greater understanding. This suggests the involvement of pathways or mechanisms for the development of SpA that remain unknown. In order to allow a wide use of IL-23 inhibitors, further clinical trials and long-term prospective studies are necessary.
Aquatic food allergy has become a key food safety problem and therefore it is urgent to study the mechanism of aquatic food allergy. Turbot parvalbumin (PV) is a major marine food allergen that could cause allergic reactions but the cellular and molecular mechanisms remain to be defined. In this study, we used flow cytometry and ELISA, a coupled co-culture system of dendritic cells and T cells, and revealed that PV could promote the maturation of dendritic cells, mainly by inducing bone marrow-derived dendritic cells (BMDCs) to express MHC II and CD86, and promote the cytokines/chemokines IL-6, IFN-γ, IL-23, and IL-12p70, whereas inhibiting TNF-α expression. Our results suggested that murine BMDCs play a crucial role in the effect of PV on the induction of Th2 responses.
We investigated the possibility that T helper cells might enhance the stimulatory function of dendritic cells (DCs). We found that ligation of CD40 by CD40L triggers the production of extremely high levels ofbioactive IL-12. Other stimuli such as microbial agents, TNF-cx or LPS are much less effective or not at all. In addition, CD40L is the most potent stimulus in upregu-lating the expression ofICAM-1, CD80, and CD86 molecules on DCs. These effects of CD40 ligation result in an increased capacity of DCs to trigger proliferative responses and IFN-~/pro-duction by T cells. These findings reveal a new role for CD40-CD40L interaction in regulating DC function and are relevant to design therapeutic strategies using cultured DCs.
Crohn's disease is associated with excess cytokine activity mediated by type 1 helper T (Th1) cells. Interleukin-12 is a key cytokine that initiates Th1-mediated inflammatory responses.
This double-blind trial evaluated the safety and efficacy of a human monoclonal antibody against interleukin-12 (anti-interleukin-12) in 79 patients with active Crohn's disease. Patients were randomly assigned to receive seven weekly subcutaneous injections of 1 mg or 3 mg of anti-interleukin-12 per kilogram of body weight or placebo, with either a four-week interval between the first and second injection (Cohort 1) or no interruption between the two injections (Cohort 2). Safety was the primary end point, and the rates of clinical response (defined by a reduction in the score for the Crohn's Disease Activity Index [CDAI] of at least 100 points) and remission (defined by a CDAI score of 150 or less) were secondary end points.
Seven weeks of uninterrupted treatment with 3 mg of anti-interleukin-12 per kilogram resulted in higher response rates than did placebo administration (75 percent vs. 25 percent, P=0.03). At 18 weeks of follow-up, the difference in response rates was no longer significant (69 percent vs. 25 percent, P=0.08). Differences in remission rates between the group given 3 mg of anti-interleukin-12 per kilogram and the placebo group in Cohort 2 were not significant at either the end of treatment or the end of follow-up (38 percent and 0 percent, respectively, at both times; P=0.07). There were no significant differences in response rates among the groups in Cohort 1. The rates of adverse events among patients receiving anti-interleukin-12 were similar to those among patients given placebo, except for a higher rate of local reactions at injection sites in the former group. Decreases in the secretion of interleukin-12, interferon-gamma, and tumor necrosis factor alpha by mononuclear cells of the colonic lamina propria accompanied clinical improvement in patients receiving anti-interleukin-12.
Treatment with a monoclonal antibody against interleukin-12 may induce clinical responses and remissions in patients with active Crohn's disease. This treatment is associated with decreases in Th1-mediated inflammatory cytokines at the site of disease.
To detect novel molecules involved in immune functions, a subtracted cDNA library between closely related murine lymphoid cells was prepared using improved technology. Differential screening of this library yielded several clones with a very restricted tissue specificity, including one that we named CTLA-8. CTLA-8 transcripts could be detected only in T cell hybridoma clones related to the one used to prepare the library. Southern blots showed that the CTLA-8 gene was single copy in mice, rats, and humans. By radioactive in situ hybridization, the CTLA-8 gene was mapped at a single site on mouse chromosome 1A and human chromosome 2q31, in a known interspecific syntenic region. The CTLA-8 cDNA sequence indicated the presence, in the 3'-untranslated region of the mRNA, of AU-rich repeats previously found in the mRNA of various cytokines, growth factors, and oncogenes. The CTLA-8 cDNA contained an open reading frame encoding a putative protein of 150 amino acids. This protein was 57% homologous to the putative protein encoded by the ORF13 gene of herpesvirus Saimiri, a T lymphotropic virus. These findings are discussed in the context of other genes of this herpesvirus homologous to known immunologically active molecules. More generally, CTLA-8 may belong to the growing set of virus-captured functionally important cellular genes related to the immune system or to cell death and cell survival.
Experimental autoimmune uveitis (EAU) is a T cell-mediated disease that targets the neural retina and serves as a model of human uveitis. Uveitogenic effector T cells have a Th1-like phenotype (high IFN-gamma, low IL-4), and genetic susceptibility to EAU is associated with an elevated Th1 response. Here we investigate whether the ability to produce IFN-gamma is necessary for the development of EAU by immunizing IFN-gamma-deficient (GKO) mice with the uveitogenic protein interphotoreceptor retinoid binding protein (IRBP) and characterize the associated immunologic responses. GKO mice developed EAU comparable in severity and incidence to that of their wild-type littermates. However, the cytokine profile in their uveitic eyes as well as the cytokines produced by primed lymph node cells in response to IRBP showed a distinct profile: undiminished TNF-alpha and elevated IL-5, IL-6, IL-10, and lymphotoxin (but not IL-4) responses. The inflammatory infiltrate in GKO eyes contained an excess of granulocytes and IL-5- and IL-6-producing cells, but uveitic GKO mice did not up-regulate inducible nitric oxide synthase. GKOs had enhanced lymphocyte proliferation and delayed-type hypersensitivity responses to IRBP. Histology of the delayed-type hypersensitivity lesion in GKO had superimposed elements of an allergic-like response. Anti-IRBP Ab isotypes of GKO mice showed a reduction of IgG2a, but no enhancement of IgG1. Comparison of responses in +/+ and +/- wild-type mice revealed some limited evidence of a gene-dose effect. We conclude that IFN-gamma is not required for priming of pathogenic T cells or for effecting the retinal damage and photoreceptor loss typical of EAU. However, what appears to be a grossly similar disease is caused in the GKO by a deviant type of effector response.
CSF-1 and TNF-alpha in the kidney of MRL-Fas(lpr) mice are proximal events that precede and promote autoimmune lupus nephritis, while apoptosis of renal parenchymal cells is a feature of advanced human lupus nephritis. In the MRL-Fas(lpr) kidney, infiltrating T cells that secrete IFN-gamma are a hallmark of disease. To examine the impact of IFN-gamma on renal injury in MRL-Fas(lpr) mice, we constructed a IFN-gamma R-deficient strain. In MRL-Fas(lpr) mice lacking IFN-gamma R, circulating and intrarenal CSF-1 were absent, TNF-alpha was markedly reduced, survival was extended, lymphadenopathy and splenomegaly were prevented, and the kidneys remained protected from destruction. Mesangial cells (MC) that were signaled through the IFN-gamma R induced CSF-1 and TNF-alpha in MRL-Fas(lpr) mice. We detected a large number of apoptotic renal parenchymal cells in advanced nephritis and determined that signaling via the IFN-gamma R induces apoptosis of tubular epithelial cells (TEC), but not MC. By comparison, TNF-alpha induces apoptosis in MC, but not TEC, of the MRL-Fas(lpr) strain. Thus, IFN-gamma is directly and indirectly responsible for apoptosis of TEC and MC in MRL-Fas(lpr) mice, respectively. In conclusion, IFN-gamma R signaling is essential for the initiation (CSF-1), acceleration (CSF-1 and TNF-alpha), and apoptotic destruction of renal parenchymal cells in MRL-Fas(lpr) autoimmune kidney disease.
IL-17 is a newly discovered T cell-derived cytokine whose role in osteoclast development has not been fully elucidated. Treatment of cocultures of mouse hemopoietic cells and primary osteoblasts with recombinant human IL-17 induced the formation of multinucleated cells, which satisfied major criteria of osteoclasts, including tartrate-resistant acid phosphatase activity, calcitonin receptors, and pit formation on dentine slices. Direct interaction between osteoclast progenitors and osteoblasts was required for IL-17-induced osteoclastogenesis, which was completely inhibited by adding indomethacin or NS398, a selective inhibitor of cyclooxgenase-2 (COX-2). Adding IL-17 increased prostaglandin E2 (PGE2) synthesis in cocultures of bone marrow cells and osteoblasts and in single cultures of osteoblasts, but not in single cultures of bone marrow cells. In addition, IL-17 dose-dependently induced expression of osteoclast differentiation factor (ODF) mRNA in osteoblasts. ODF is a membrane-associated protein that transduces an essential signal(s) to osteoclast progenitors for differentiation into osteoclasts. Osteoclastogenesis inhibitory factor (OCIF), a decoy receptor of ODF, completely inhibited IL-17-induced osteoclast differentiation in the cocultures. Levels of IL-17 in synovial fluids were significantly higher in rheumatoid arthritis (RA) patients than osteoarthritis (OA) patients. Anti-IL-17 antibody significantly inhibited osteoclast formation induced by culture media of RA synovial tissues. These findings suggest that IL-17 first acts on osteoblasts, which stimulates both COX-2-dependent PGE2 synthesis and ODF gene expression, which in turn induce differentiation of osteoclast progenitors into mature osteoclasts, and that IL-17 is a crucial cytokine for osteoclastic bone resorption in RA patients.
Ligation of CD40 on dendritic cells (DC) triggers production of IL-12. Using an adoptive transfer model we have previously shown that rIL-12 acts directly on DC to enhance presentation of an otherwise poorly immunogenic tumor peptide. Using the same experimental model, we now describe a similar adjuvanticity of CD40 ligation on peptide presentation by DC. We also explore the possibility that the IL-12 resulting from CD40 ligation directly affects the APC function of DC, mediating or contributing to the adjuvant effect of CD40 ligation. CD40 engagement in vitro and rIL-12 at concentrations in the range induced by CD40 ligation were equally effective in priming DC for presentation of the tumor peptide in vivo. Remarkably, the copresence in vitro of neutralizing Ab to IL-12, but not to TNF-alpha, IL-1beta, or IFN-gamma, ablated the enhancing effect of CD40 engagement on the APC function of DC. These data suggest a major role for autocrine IL-12 in DC modulation via CD40 ligation.
Experimental autoimmune encephalomyelitis (EAE) is mediated by myelin-specific CD4(+) T cells secreting Th1 cytokines, while recovery from disease is associated with expression of Th2 cytokines. Investigations into the role of individual cytokines in disease induction have yielded contradictory results. Here we used animals with targeted deletion of the STAT4 or STAT6 genes to determine the role of these signaling molecules in EAE. The STAT4 pathway controls the differentiation of cells into a Th1 phenotype, while the STAT6 pathway controls the differentiation of cells into a Th2 phenotype. We found that mice deficient in STAT4 are resistant to the induction of EAE, with minimal inflammatory infiltrates in the central nervous system. In contrast, STAT6-deficient mice, which have a predominantly Th1 phenotype, experience a more severe clinical course of EAE as compared with wild-type or STAT4 knockout mice. In addition, adoptive transfer studies confirm the regulatory functions of a Th2 environment in vivo. These novel data indicate that STAT4 and STAT6 genes play a critical role in regulating the autoimmune response in EAE.
T helper type 1 (T(H)1) cell development involves interferon-gamma (IFN-gamma) signaling through signal transducer and activator of transcription 1 (STAT1) and interleukin-12 (IL-12) signaling through STAT4 activation. We examined here T-bet regulation and evaluated the actions of T-bet in STAT1- and STAT4-dependent T(H)1 development processes. We found that T-bet expression during T cell activation was strongly dependent on IFN-gamma signaling and STAT1 activation, but was independent of STAT4. Ectopic T-bet expression strongly increased IFN-gamma production in T(H)2 cells activated by PMA-ionomycin, but weakly increased IFN-gamma production in T(H)2 cells stimulated by IL-12 IL-18 or OVA peptide antigen-presenting cell stimulation. In contrast, IL-12 IL-18 induced IFN-gamma production remained STAT4-dependent despite ectopic T-bet expression. Ectopic T-bet expression selectively induced expression of IL-12Rbeta2, but not IL-18Ralpha, in wild-type and STAT1(-/-) T(H)2 cells, but did not extinguish expression of GATA-3 and T(H)2 cytokines. Finally, ectopic T-bet did not directly induce expression of endogenous T- bet independently of IFN-gamma or STAT1. Thus, T-bet is induced by IFN-gamma and STAT1 signaling during T cell activation. In addition, T-bet mediates STAT1-dependent processes of T(H)1 development, including the induction of IL-12Rbeta2.
Various microbial, inflammatory and immune signals regulate the activation of dendritic cells (DC), determining their ability to interact with naïve T cells and to produce cytokines that direct T cell development. In particular, CD40L and IL-1 cooperatively activate DC to secrete high levels of IL-12. The immuno-stimulatory capacity of such DC is otherwise not well-defined prompting further characterization of the effects of IL-1 and family members on DC activation in comparison with other pro-inflammatory stimuli.
Human DC co-activated in vitro by CD40L and IL-1beta expressed numerous cytokine genes including IL-12beta, IL-23 p19, IL-1beta, IL-1alpha, IL-1Ra, IL-10, IL-6, IL-18 and IFN-gamma. These DC produced high levels of IL-12 protein and appeared capable of producing IFN-gamma. Potent CD4+ and CD8+ T cell-stimulatory properties were acquired by DC under conditions that also induced IL-12. Notably, these DC induced rapid differentiation of fluMP-specific CD8+ T cells. Molecules related to IL-1beta, like IL-1alpha, co-induced IL-12 secretion whereas IL-18 did not. Conversely, the inhibitor IL-1Ra, produced endogenously by DC curtailed IL-12 production in response to CD40L.
IL-1 and IL-1Ra play a biologically-relevant role in the positive and negative regulation of DC activation. In conjunction with CD40L, IL-1 sends a powerful activation signal to DC that could be distinguished from other modes of activation. This signal enables the production of pro-inflammatory cytokines by DC, and enhances the differentiation of naïve T cells into effectors of type-1 cellular immune responses.
IL-12 is thought to be involved in the susceptibility to experimental autoimmune encephalomyelitis (EAE), a Th1 cell-mediated autoimmune disorder of the CNS. IL-12 signals through a heterodimeric receptor (IL-12Rbeta1/IL-12Rbeta2), whose beta2-chain is up-regulated on activated, autoreactive Th1 cells. Contrary to the expectation that the absence of IL-12Rbeta2 would protect from EAE, we found that IL-12Rbeta2-deficient mice developed earlier and more severe disease, with extensive demyelination and CNS inflammation. The inflammatory cells were mainly comprised of CD4(+) T cells, monocyte/macrophages, and dendritic cells. Compared to wild-type mice, IL-12Rbeta2-deficient mice exhibited significantly increased autoantigen-induced proliferative response and increased production of TNF-alpha, GM-CSF, IL-17, IL-18/IL-18Ralpha, and NO. In addition, we found significantly increased levels of IL-23p19 mRNA expression in spleen cells from immunized IL-12Rbeta2(-/-) mice compared with wild-type mice. These findings indicate that IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the CNS, and that, in the absence of IL-12Rbeta2, increased IL-23 and other inflammatory molecules may be responsible for increased severity of EAE.
Interleukin-12 (IL-12) is a heterodimeric molecule composed of p35 and p40 subunits. Analyses in vitro have defined IL-12 as an important factor for the differentiation of naive T cells into T-helper type 1 CD4+ lymphocytes secreting interferon-gamma (refs 1, 2). Similarly, numerous studies have concluded that IL-12 is essential for T-cell-dependent immune and inflammatory responses in vivo, primarily through the use of IL-12 p40 gene-targeted mice and neutralizing antibodies against p40. The cytokine IL-23, which comprises the p40 subunit of IL-12 but a different p19 subunit, is produced predominantly by macrophages and dendritic cells, and shows activity on memory T cells. Evidence from studies of IL-23 receptor expression and IL-23 overexpression in transgenic mice suggest, however, that IL-23 may also affect macrophage function directly. Here we show, by using gene-targeted mice lacking only IL-23 and cytokine replacement studies, that the perceived central role for IL-12 in autoimmune inflammation, specifically in the brain, has been misinterpreted and that IL-23, and not IL-12, is the critical factor in this response. In addition, we show that IL-23, unlike IL-12, acts more broadly as an end-stage effector cytokine through direct actions on macrophages.
Dendritic cells (DCs) are a family of leukocytes that initiate T- and B-cell immunity against pathogens. Migration of antigen-loaded DCs from sites of infection into draining lymphoid tissues is fundamental to the priming of T-cell immune responses. In humans, the major peripheral blood DC (PBDC) types, CD1c+ DCs and interleukin 3 receptor-positive (IL-3R+) plasmacytoid DCs, are significantly expanded in vivo with the use of Flt3 ligand (FL). DC-like cells can also be generated from monocyte precursors (MoDCs). A detailed comparison of the functional potential of these types of DCs (in an autologous setting) has yet to be reported. Here, we compared the functional capacity of FL-expanded CD1c+ PBDCs with autologous MoDCs in response to 3 different classes of stimuli: (1) proinflammatory mediators, (2) soluble CD40 ligand trimer (CD40L), and (3) intact bacteria (Escherichia coli). Significant differences in functional capacities were found with respect to changes in phenotype, migratory capacity, cytokine secretion, and T-cell stimulation. MoDCs required specific stimuli for the expression of functions. They responded vigorously to CD40L or E coli, expressing cytokines known to regulate interferon-gamma (IFN-gamma) in T cells (IL-12p70, IL-18, and IL-23), but required prostaglandin E2 (PGE2) during stimulation to migrate to chemokines. In contrast, PBDCs matured in response to minimal stimulation, rapidly acquired migratory function in the absence of PGE2-containing stimuli, and were low cytokine producers. Interestingly, both types of DCs were equivalent with respect to stimulation of allogeneic T-cell proliferation and presentation of peptides to cytotoxic T lymphocyte (CTL) lines. These distinct differences are of particular importance when considering the choice of DC types for clinical applications.
IL-12 p40-related cytokines such as IL-12 p35/p40 heterodimer and IL-23 (p19/p40) are potent regulators of adaptive immune responses. Little is known, however, about the transcriptional regulation of the p40 gene in vivo. In an attempt toward this goal, we have generated transgenic mice expressing firefly luciferase under the control of the IL-12 p40 promoter. High constitutive transgene expression was found in the small intestine only, whereas little reporter gene activity was observed in other tissues. Within the small bowel, constitutive promoter activity was restricted to the terminal ileum and associated with high expression of p40 mRNA as well as p40 and IL-23 p19/p40 proteins. The cells constitutively producing IL-12 p40 were identified as CD8alpha and CD11b double-negative CD11c+ lamina propria dendritic cells (LPDCs) that represent a major cell population in the lamina propria of the small intestine, but not in the colon. FISH directly demonstrated the uptake of bacteria by a subset of LPDCs in the terminal ileum that was associated with p40 expression. Furthermore, little or no p40 protein expression in LPDCs was found in the terminal ileum of germfree mice, indicating a key role of the intestinal flora for constitutive p40 expression. In addition, analysis of transgenic mice with a mutated NF-kappaB target site in the p40 promoter showed a critical role of NF-kappaB for constitutive transgene expression. Our data reveal important functional differences between the mucosal immune systems of the small and large bowel in healthy mice and suggest that the high bacterial load in the terminal ileum activates p40 gene transcription in LPDCs through NF-kappaB. These data suggest a predisposition of the terminal ileum to develop chronic inflammatory responses through IL-23 and thus may provide a molecular explanation for the preferential clinical manifestation of Crohn disease in this part of the gut.
Psoriasis is a type I-deviated disease characterized by the presence of interferon (IFN)-gamma and multiple IFN-related inflammatory genes in lesions. Because interleukin (IL)-23 is now recognized to play a role in the recruitment of inflammatory cells in a T helper cell (Th)1-mediated disease, we examined psoriasis skin lesions for production of this newly described cytokine. IL-23 is composed of two subunits: a unique p19 subunit and a p40 subunit shared with IL-12. We found a reliable increase in p19 mRNA by quantitative reverse transcription polymerase chain reaction in lesional skin compared with nonlesional skin (22.3-fold increase; P = 0.001). The p40 subunit, shared by IL-12 and IL-23, increased by 11.6-fold compared with nonlesional skin (P = 0.003), but the IL-12 p35 subunit was not increased in lesional skin. IL-23 was expressed mainly by dermal cells and increased p40 immunoreactivity was visualized in large dermal cells in the lesions. Cell isolation experiments from psoriatic tissue showed strong expression of p19 mRNA in cells expressing monocyte (CD14+ CD11c+ CD83-) and mature dendritic cell (DC) markers (CD14- CD11c+ CD83+), whereas in culture, the mRNAs for p40 and p19 were strongly up-regulated in stimulated monocytes and monocyte-derived DCs, persisting in the latter for much longer periods than IL-12. Our data suggest that IL-23 is playing a more dominant role than IL-12 in psoriasis, a Th1 type of human inflammatory disease.
Macrophages (Mphi) play a central role as effector cells in immunity to intracellular pathogens such as Mycobacterium. Paradoxically, they also provide a habitat for intracellular bacterial survival. This paradoxical role of Mphi remains poorly understood. Here we report that this dual role may emanate from the functional plasticity of Mphi: Whereas Mphi-1 polarized in the presence of granulocyte-Mphi colony-stimulating factor promoted type 1 immunity, Mphi-2 polarized with Mphi colony-stimulating factor subverted type 1 immunity and thus may promote immune escape and chronic infection. Importantly, Mphi-1 secreted high levels of IL-23 (p40/p19) but no IL-12 (p40/p35) after (myco)bacterial activation. In contrast, activated Mphi-2 produced neither IL-23 nor IL-12 but predominantly secreted IL-10. Mphi-1 required IFN-gamma as a secondary signal to induce IL-12p35 gene transcription and IL-12 secretion. Activated dendritic cells produced both IL-12 and IL-23, but unlike Mphi-1 they slightly reduced their IL-23 secretion after addition of IFN-gamma. Binding, uptake, and outgrowth of a mycobacterial reporter strain was supported by both Mphi subsets, but more efficiently by Mphi-2 than Mphi-1. Whereas Mphi-1 efficiently stimulated type 1 helper cells, Mphi-2 only poorly supported type 1 helper function. Accordingly, activated Mphi-2 but not Mphi-1 down-modulated their antigen-presenting and costimulatory molecules (HLA-DR, CD86, and CD40). These findings indicate that (i) Mphi-1 and Mphi-2 play opposing roles in cellular immunity and (ii) IL-23 rather than IL-12 is the primary type 1 cytokine produced by activated proinflammatory Mphi-1. Mphi heterogeneity thus may be an important determinant of immunity and disease outcome in intracellular bacterial infection.
The transcription factors signal transducer and activator of transcription (STAT)1 and T-bet control the differentiation of interferon (IFN)-gamma-producing T helper type (Th)1 cells. Here we compare the role of T-bet and STAT1 in the initiation and regulation of experimental autoimmune encephalomyelitis (EAE), a disease initiated by Th1 cells. T-bet-deficient mice immunized with myelin oligodendrocyte glycoprotein (MOG) were resistant to the development of EAE. This protection was also observed when T-bet(-/-) mice were crossed to the MOG-specific 2D2 T cell receptor transgenic strain. In contrast, although T-bet is downstream of STAT1, STAT1(-/-) mice were highly susceptible to EAE and developed more severe and accelerated disease with atypical neuropathologic features. The function of T-bet was dominant as mice deficient in both T-bet and STAT1 were also protected from EAE. CD4(+) CD25(+) regulatory T cells from these two mice strains were fully competent and do not explain the difference in disease susceptibility. However, enhanced EAE in STAT1(-/-) mice was associated with continued generation of IFN-gamma-producing Th1 cells and up-regulation of selective chemokines responsible for the increased recruitment of macrophages and neutrophils in the central nervous system. Although the two transcription factors, STAT1 and T-bet, both induce IFN-gamma gene transcription, our results demonstrate marked differences in their function in regulating pathogenic Th1 cell responses.
IL-23 and IL-12 are heterodimeric cytokines which share the p40 subunit, but which have unique second subunits, IL-23p19 and IL-12p35. Since p40 is required for the development of the Th1 type response necessary for resistance to Toxoplasma gondii, studies were performed to assess the role of IL-23 in resistance to this pathogen. Increased levels of IL-23 were detected in mice infected with T. gondii and in vitro stimulation of dendritic cells with this pathogen resulted in increased levels of mRNA for this cytokine. To address the role of IL-23 in resistance to T. gondii, mice lacking the p40 subunit (common to IL-12 and IL-23) and mice that lack IL-12 p35 (specific for IL-12) were infected and their responses were compared. These studies revealed that p40(-/-) mice rapidly succumbed to toxoplasmosis, while p35(-/-) mice displayed enhanced resistance though they eventually succumbed to this infection. In addition, the administration of IL-23 to p40(-/-) mice infected with T. gondii resulted in a decreased parasite burden and enhanced resistance. However, the enhanced resistance of p35(-/-) mice or p40(-/-) mice treated with IL-23 was not associated with increased production of IFN-gamma. When IL-23p19(-/-) mice were infected with T. gondii these mice developed normal T cell responses and controlled parasite replication to the same extent as wild-type mice. Together, these studies indicate that IL-12, not IL-23, plays a dominant role in resistance to toxoplasmosis but, in the absence of IL-12, IL-23 can provide a limited mechanism of resistance to this infection.
Interleukin (IL)-17 is a pro-inflammatory cytokine that is produced by activated T cells. Despite increasing evidence that
high levels of IL-17 are associated with several chronic inflammatory diseases including rheumatoid arthritis, psoriasis,
and multiple sclerosis, the regulation of its expression is not well characterized. We observe that IL-17 production is increased
in response to the recently described cytokine IL-23. We present evidence that murine IL-23, which is produced by activated
dendritic cells, acts on memory T cells, resulting in elevated IL-17 secretion. IL-23 also induced expression of the related
cytokine IL-17F. IL-23 is a heterodimeric cytokine and shares a subunit, p40, with IL-12. In contrast to IL-23, IL-12 had
only marginal effects on IL-17 production. These data suggest that during a secondary immune response, IL-23 can promote an
activation state with features distinct from the well characterized Th1 and Th2 profiles.
The interleukin-12 (IL-12) cytokine family plays important roles in the orchestration of innate and adaptive immunity by dendritic cells (DCs). The regulation of IL-12 expression has been thoroughly studied, but little is known about factors governing the expression of IL-23 and IL-27, 2 novel IL-12 family members acting on memory and naive T cells, respectively. We report that the expression of these cytokines by DCs was critically dependent on the mode of activation. DC activation by CD40L predominantly induced IL-12. Ligands of the Toll-like receptor (TLR) 3 and TLR4 induced IL-12 and IL-27, whereas exposure to intact Escherichia coli resulted in high expression of IL-12, IL-27, and IL-23. The nucleotide adenosine triphosphate (ATP) has been shown to inhibit IL-12 production by P2 receptors. We found that ATP also inhibited IL-27 expression but enhanced IL-23 expression. Interestingly, the reciprocal regulation of IL-12/IL-27 and IL-23 by ATP was mediated by 2 distinct P2 receptors and was also induced by prostaglandin E(2) by cyclic adenosine monophosphate (cAMP)-elevating EP2/EP4 receptors. As a consequence, DCs were selectively impaired in their ability to induce interferon-gamma (IFN-gamma) in naive T cells but continued to promote IFN-gamma and IL-17 production in memory T cells. These studies identify P2 receptors as promising targets for the design of novel strategies to manipulate specific stages of T-cell responses and to treat IL-12- and IL-23-mediated disorders.
Interleukin (IL)-23 is a heterodimeric cytokine composed of a unique p19 subunit, and a common p40 subunit shared with IL-12. IL-12 is important for the development of T helper (Th)1 cells that are essential for host defense and tumor suppression. In contrast, IL-23 does not promote the development of interferon-gamma-producing Th1 cells, but is one of the essential factors required for the expansion of a pathogenic CD4(+) T cell population, which is characterized by the production of IL-17, IL-17F, IL-6, and tumor necrosis factor. Gene expression analysis of IL-23-driven autoreactive T cells identified a unique expression pattern of proinflammatory cytokines and other novel factors, distinguishing them from IL-12-driven T cells. Using passive transfer studies, we confirm that these IL-23-dependent CD4(+) T cells are highly pathogenic and essential for the establishment of organ-specific inflammation associated with central nervous system autoimmunity.
Bordetella pertussis, the causative agent of whooping cough, is internalized by several cell types, including epithelial cells, monocytes, and
neutrophils. Although its ability to survive intracellularly is still debated, it has been proven that cell-mediated immunity
(CMI) plays a pivotal role in protection. In this study we aimed to clarify the interaction of B. pertussis with human monocyte-derived dendritic cells (MDDC), evaluating the ability of the bacterium to enter MDDC, to survive intracellularly,
to interfere with the maturation process and functional activities, and to influence the host immune responses. The results
obtained showed that B. pertussis had a low capability to be internalized by—and to survive in—MDDC. Upon contact with the bacteria, immature MDDC were induced
to undergo phenotypic maturation and acquired antigen-presenting-cell functions. Despite the high levels of interleukin-10
(IL-10) and the barely detectable levels of IL-12 induced by B. pertussis, the bacterium induced maturation of MDDC and T helper 1 (Th1) polarized effector cells. Gene expression analysis of the
IL-12 cytokine family clearly demonstrated that B. pertussis induced high levels of the p40 and p19 subunits of IL-23 yet failed to induce the expression of the p35 subunit of IL-12.
Overall our findings show that B. pertussis, even if it survives only briefly in MDDC, promotes the synthesis of IL-23, a newly discovered Th1 polarizing cytokine. A
Th1-oriented immune response is thus allowed, relevant in the induction of an adequate CMI response, and typical of protection
induced by natural infection or vaccination with whole-cell vaccines.
CpG oligodeoxynucleotides (ODNs) may prevent mortality from infection. We have identified a therapeutic benefit in treating
sepsis with phosphorothioate ODN sequences containing the CpG motif. Sepsis was induced in rats by cecal ligation and puncture
(CLP), and treatment with CpG ODNs reduced sepsis mortality from 80% to 15% during a 108-h period. Protection from mortality
was dose dependent. Bacterial load in peritoneal fluid was reduced in CpG ODN–treated versus non-CpG ODN–treated rats after
CLP. Lung injury, as determined by total myeloperoxidase activity, was also reduced in CpG ODN–treated versus non-CpG ODN–treated
rats after CLP. Indirect evidence suggests that CpG-induced expression of interleukin (IL)–23 as levels of p40—but not p35—were
significantly increased in both plasma and peritoneal lavage fluid in CpG ODN–treated versus non-CpG ODN–treated rats 24 h
after CLP. Anti–IL-17 antibody inhibited the CpG-mediated prevention of mortality. These data suggest that IL-17 may mediate
CpG-inducible host defenses during intraabdominal sepsis
Myelin-directed autoimmunity is considered to Ploy a key role in the pathogenesis of multiple sclerosis (MS). increased Production of both pro- and anti-inflammatory cytokines is a common finding in MS. Interleukin-17 (IL-17) is a recently described cytokine produced in humans almost exclusively by activated memory T cells, which con induce the production of proinflammatory cytokines and chemokines from parenchymal cells and macrophages. In situ hybridisation with synthetic oligonucleotide probes was adopted to detect and enumerate IL-17 mRNA expressing mononuclear cells (MNC) in blood and cerebrospinal fluid (CSF) from patients with MS and control individuals. Numbers of IL-17 mRNA expressing blood MNC were higher in patients with MS and acute aseptic meningoencephalitis (AM) compared to healthy individuals. Higher numbers of IL-17 mRNA expressing blood MNC were detected in MS patients examined during clinical exacerbation compared to remission. Patients with MS had higher numbers of IL-17 mRNA expressing MNC in CSF compared to blood. This increase in numbers of IL-17 mRNA expressing MNC in CSF was not observed in patients with AM. Our results thus demonstrate increased numbers of IL-17 mRNA expressing MNC in MS with higher numbers in CSF than blood, and with the highest numbers in blood during clinical exacerbations.
As a means of developing therapies that target the pathogenic T cells in multiple sclerosis (MS) without compromising the immune system or eliciting systemic side effects, we investigated the use of T-bet-specific antisense oligonucleotides and small interfering RNAs (siRNA) to silence T-bet expression in autoreactive encephalitogenic T cells and evaluated the biological consequences of this suppression in experimental autoimmune encephalomyelitis, a model for MS. The T-bet-specific AS oligonucleotide and siRNA suppressed T-bet expression, IFNgamma production, and STAT1 levels during antigen-specific T cell differentiation. In vitro suppression of T-bet during differentiation of myelin-specific T cells and in vivo administration of a T-bet-specific antisense oligonucleotide or siRNA inhibited disease. T-bet was shown to bind the IFNgamma and STAT1 promoters, but did not regulate the IL-12/STAT4 pathway. Since T-bet regulates IFNgamma production in CD4(+) T cells, but to a lesser extent in most other IFNgamma-producing cells, T-bet may be a target for therapeutics for Th1-mediated diseases.
A panel of antigen-specific mouse helper T cell clones was characterized according to patterns of lymphokine activity production, and two types of T cell were distinguished. Type 1 T helper cells (TH1) produced IL 2, interferon-gamma, GM-CSF, and IL 3 in response to antigen + presenting cells or to Con A, whereas type 2 helper T cells (TH2) produced IL 3, BSF1, and two other activities unique to the TH2 subset, a mast cell growth factor distinct from IL 3 and a T cell growth factor distinct from IL 2. Clones representing each type of T cell were characterized, and the pattern of lymphokine activities was consistent within each set. The secreted proteins induced by Con A were analyzed by biosynthetic labeling and SDS gel electrophoresis, and significant differences were seen between the two groups of T cell line. Both types of T cell grew in response to alternating cycles of antigen stimulation, followed by growth in IL 2-containing medium. Examples of both types of T cell were also specific for or restricted by the I region of the MHC, and the surface marker phenotype of the majority of both types was Ly-1+, Lyt-2-, L3T4+, Both types of helper T cell could provide help for B cells, but the nature of the help differed. TH1 cells were found among examples of T cell clones specific for chicken RBC and mouse alloantigens. TH2 cells were found among clones specific for mouse alloantigens, fowl gamma-globulin, and KLH. The relationship between these two types of T cells and previously described subsets of T helper cells is discussed.
Experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, is an autoimmune disorder seen in mice and rats following immunization with myelin basic protein (MBP) or MBP-derived peptides. IFN-gamma, a cytokine produced by a variety of cells, is involved in many inflammatory and immune regulatory events. Contradictory results concerning exacerbations and the disease course were seen comparing injections of IFN-gamma in humans suffering from multiple sclerosis to studies using anti-IFN-gamma Abs in mice with EAE. To study the role of IFN-gamma and IFN-gamma-producing cells in EAE, we crossed IFN-gamma knockout mice (H-2b) (unable to produce IFN-gamma due to the disruption of the IFN-gamma gene) with an EAE-susceptible mouse strain, B10.PL (H-2u). EAE was seen in IFN-gamma knockout mice, heterozygotic (IFN-gamma +/-) mice, as well as wild-type littermates following immunization with MBP. Histologic analyses of the central nervous system of IFN-gamma knockout mice with EAE revealed massive infiltrates composed of lymphocytes, macrophages, and granulocytes. We conclude that the presence of IFN-gamma is not crucial to the induction or the clinical course of EAE.
We investigated the possibility that T helper cells might enhance the stimulatory function of dendritic cells (DCs). We found that ligation of CD40 by CD40L triggers the production of extremely high levels of bioactive IL-12. Other stimuli such as microbial agents, TNF-alpha or LPS are much less effective or not at all. In addition, CD40L is the most potent stimulus in upregulating the expression of ICAM-1, CD80, and CD86 molecules on DCs. These effects of CD40 ligation result in an increased capacity of DCs to trigger proliferative responses and IFN-gamma production by T cells. These findings reveal a new role for CD40-CD40L interaction in regulating DC function and are relevant to design therapeutic strategies using cultured DCs.
In experimental allergic encephalomyelitis (EAE), T cells infiltrate the central nervous system (CNS) and induce inflammation. These CD4+ T cells secrete interferon (IFN)-gamma, levels of which correlate with disease severity, and which is proposed to play a key role in disease induction. Many strains of mice are resistant to EAE. We have studied the effect of deletion of IFN-gamma on the ability to induce EAE in resistant BALB/c-backcrossed mice. As expected, only 0-6% of BALB/c or BALB/c-backcrossed mice developed EAE when immunized with myelin basic protein in adjuvant. Strikingly, abrogation of IFN-gamma expression by targeted disruption of the IFN-gamma gene (GKO mice) converted them to a susceptible phenotype. As many as 71% of these IFN-gamma-deficient mice developed EAE, a frequency comparable to that seen with the susceptible SJL/J strain. In addition, EAE was of unusually high severity in mice lacking IFN-gamma. Immunological characteristics of disease in IFN-gamma-deficient mice were comparable to those seen in susceptible (SJL/J) mice with EAE, including perivascular infiltration in the CNS and order-of-magnitude increases for both CD3 gamma chain and TNF-alpha mRNA levels in the spinal cord. We thus demonstrate that lack of IFN-gamma converts an otherwise EAE-resistant mouse strain to become susceptible to disease. Therefore, in BALB/c mice, IFN-gamma confers resistance to EAE.
The systemic autoimmune syndrome of MRL/Mp-lpr/lpr (MRL/lpr) mice consists of severe pan-isotype hypergammaglobulinemia, autoantibody production, lymphadenopathy, and immune complex-associated end-organ disease. Its pathogenesis has been largely attributed to helper alphabeta T cells that may require critical cytokines to propagate pathogenic autoantibody production. To investigate the roles of prototypical Th1 and Th2 cytokines in the pathogenesis of murine lupus, IFN-gamma -/- and IL-4 -/- lupus-prone mice were generated by backcrossing cytokine knockout animals against MRL/lpr breeders. IFN-gamma -/- animals produced significantly reduced titers of IgG2a and IgG2b serum immunoglobulins as well as autoantibodies, but maintained comparable levels of IgG1 and IgE in comparison to cytokine-intact controls; in contrast, IL-4 -/- animals produced significantly less IgG1 and IgE serum immunoglobulins, but maintained comparable levels of IgG2a and IgG2b as well as autoantibodies in comparison to controls. Both IFN-gamma -/- and IL-4 -/- mice, however, developed significantly reduced lymphadenopathy and end-organ disease. These results suggest that IFN-gamma and IL-4 play opposing but dispensable roles in the development of lupus-associated hypergammaglobulinemia and autoantibody production; however, they both play prominent roles in the pathogenesis of murine lupus-associated tissue injury, as well as in lpr-induced lymphadenopathy.
Collagen-induced arthritis (CIA) is a model for rheumatoid arthritis. Here, we describe experiments showing that IFN-gamma receptor knockout (IFN-gammaR alpha KO) mice of the DBA/1 strain develop CIA more readily than their wild-type counterparts. Symptoms of disease started 10 days earlier and the cumulative incidence of arthritis was significantly higher in the mutant mice than in wild-type mice. Similarly, accelerated onset of the disease was also found in wild-type DBA/1 mice treated with neutralizing mAbs against IFN-gamma. Histologic examination of the joints revealed a massive infiltration of the synovium with mononuclear cells and neutrophils, hyperplasia, and severe pannus formation in IFN-gammaR alpha KO mice when such inflammatory lesions were not yet detectable in wild-type mice. Serum levels of anti-collagen type II Abs, including total IgG and IgM, as well as IgG1, IgG2a, and IgG2b isotypes were found to be lower in the mutant mice. IL-2 and IL-4 remained undetectable in sera of both groups of mice, but did appear in the circulation after anti-CD3 Ab challenge. Significantly higher IL-2 and lower IL-4 serum levels were found in anti-CD3-challenged IFN-gammaR alpha KO mice than in wild-type counterparts, both at an early and at a later stage of the disease. These observations indicate that endogenous IFN-gamma counteracts development of collagen-induced arthritis and suggest that IFN-gamma does so by up-regulating IL-4 production and/or down-regulating IL-2 production. The data are in line with the concept of a pathogenic role of Th1-type cellular immunity in CIA in spite of a decreased Ab response to collagen type II.
Congenic MRL-lpr mice homozygous and heterozygous for the IFN-gamma gene disruption were created to assess the role of this pleotropic cytokine on the lymphoaccumulation and lupus-like disease of Fas-defective mice. Early death was prevented, and glomerulonephritis severely reduced in IFN-gamma-/- mice. Hypergammaglobulinemia was maintained with a switch from IgG2a to IgG1 predominance, but the dramatic decrease in levels of the dominant IgG2a anti-dsDNA autoantibodies was not associated with a compensatory increase in TH2-associated IgG subclasses. Remarkably, early death and glomerulonephritis were also prevented in IFN-gamma+/- mice, although autoantibody levels and glomerular immune deposits were equivalent to IFN-gamma+/+ lpr mice, indicating the importance of additional locally-exerted disease-promoting effects of IFN-gamma. IFN-gamma-/- mice exhibited reduced lymphadenopathy concomitant to a decrease in DN B220(+) T cells. In vivo BrdU labeling showed reduced proliferation of DN B220(+) cells in IFN-gamma-/- vs. IFN-gamma+/+ lpr mice, while enhanced proliferation of all other T cell subsets was unaffected. Macrophages of IFN-gamma-/-lpr mice expressed markedly decreased levels of MHC class I and II molecules compared with controls. Moreover, the heightened expression of MHC class II molecules on proximal tubules of IFN-gamma+/+ lpr mice was significantly reduced in both IFN-gamma-/- and IFN-gamma+/- mice. The data indicate that IFN-gamma hyperproduction is required for lupus development, presumably by increasing MHC expression and autoantigen presentation to otherwise quiescent nontolerant anti-self T cells, and also by promoting local immune and inflammatory processes.
(NZB x NZW)F1 female (BW) mice spontaneously develop an autoimmune disease, characterized by the production of autoantibodies (autoAbs) and glomerulonephritis, which can be delayed by neutralizing IFN-gamma Abs and accelerated by IFN-gamma injections. To define the role of IFN-gamma in the pathogenesis of glomerulonephritis, we established a population of BW mice deficient in IFN-gammaR (BWgammaR[-/-]) by repeated crossing; these mice were compared with BWgammaR(+/+) and +/- littermates. Of the BWgammaR(+/+) and +/- mice, 50% showed immune complex glomerulonephritis with heavy proteinuria at 8 mo of age, while only 10% of the BWgammaR(-/-) mice were affected at 14 mo. The serum concentration of anti-dsDNA and anti-histone Abs was dramatically reduced in BWgammaR(-/-) mice. The role of IFN-gamma in promoting class switch to IgG2a and IgG3 could not fully account for the impaired production of anti-dsDNA in BWgammaR(-/-) animals since, IgM and IgG1 levels were also reduced. There was a high incidence of B cell lymphoma in the BWgammaR(-/-) mice, which might be related to the suppression of autoAb production. Thus, the absence of glomerulonephritis in BWgammaR(-/-) mice is likely due to a dramatic yet unexplained effect of the inactivation of IFN-gamma signaling on autoAb production.
Myelin-directed autoimmunity is considered to play a key role in the pathogenesis of multiple sclerosis (MS). Increased production of both pro- and anti-inflammatory cytokines is a common finding in MS. Interleukin-17 (IL-17) is a recently described cytokine produced in humans almost exclusively by activated memory T cells, which can induce the production of proinflammatory cytokines and chemokines from parenchymal cells and macrophages. In situ hybridisation with synthetic oligonucleotide probes was adopted to detect and enumerate IL-17 mRNA expressing mononuclear cells (MNC) in blood and cerebrospinal fluid (CSF) from patients with MS and control individuals. Numbers of IL-17 mRNA expressing blood MNC were higher in patients with MS and acute aseptic meningoencephalitis (AM) compared to healthy individuals. Higher numbers of IL-17 mRNA expressing blood MNC were detected in MS patients examined during clinical exacerbation compared to remission. Patients with MS had higher numbers of IL-17 mRNA expressing MNC in CSF compared to blood. This increase in numbers of IL-17 mRNA expressing MNC in CSF was not observed in patients with AM. Our results thus demonstrate increased numbers of IL-17 mRNA expressing MNC in MS with higher numbers in CSF than blood, and with the highest numbers in blood during clinical exacerbations.
CD40 ligation triggers IL-12 production by dendritic cells (DC) in vitro. Here, we demonstrate that CD40 cross-linking alone is not sufficient to induce IL-12 production by DC in vivo. Indeed, resting DC make neither the IL-12 p35 nor IL-12 p40 subunits and express only low levels of CD40. Nevertheless, after DC activation by microbial stimuli that primarily upregulate IL-12 p40 and augment CD40 expression, CD40 ligation induces a significant increase in IL-12 p35 and IL-12 p70 heterodimer production. Similarly, IL-12 p70 is produced during T cell activation in the presence but not in the absence of microbial stimuli. Thus, production of bioactive IL-12 by DC can be amplified by T cell-derived signals but must be initiated by innate signals.
A novel sequence discovered in a computational screen appears distantly related to the p35 subunit of IL-12. This factor, which we term p19, shows no biological activity by itself; instead, it combines with the p40 subunit of IL-12 to form a novel, biologically active, composite cytokine, which we term IL-23. Activated dendritic cells secrete detectable levels of this complex. IL-23 binds to IL-12R beta 1 but fails to engage IL-12R beta 2; nonetheless, IL-23 activates Stat4 in PHA blast T cells. IL-23 induces strong proliferation of mouse memory (CD4(+)CD45Rb(low)) T cells, a unique activity of IL-23 as IL-12 has no effect on this cell population. Similar to IL-12, human IL-23 stimulates IFN-gamma production and proliferation in PHA blast T cells, as well as in CD45RO (memory) T cells.
Dendritic cells (DC) not only stimulate T cells effectively but are also producers of cytokines that have important immune regulatory functions. In this study we have extended information on the functional differences between DC subpopulations to include differences in the production of the major immune-directing cytokines IL-12, IFN-alpha, and IFN-gamma. Splenic CD4(-)8(+) DC were identified as the major IL-12 producers in response to microbiological or T cell stimuli when compared with splenic CD4(-)8(-) or CD4(+)8(-) DC; however, all three subsets of DC showed similar IL-12 regulation and responded with increased IL-12 p70 production if IL-4 was present during stimulation. High level CD8 expression also correlated with extent of IL-12 production for DC isolated from thymus and lymph nodes. By using gene knockout mice we ruled out any role for CD8alpha itself, or of priming by T cells, on the superior IL-12-producing capacity of the CD8(+) DC. Additionally, CD8(+) DC were identified as the major producers of IFN-alpha compared with the two CD8(-) DC subsets, a finding that suggests similarity to the human plasmacytoid DC lineage. In contrast, the CD4(-)8(-) DC produced much more IFN-gamma than the CD4(-)8(+) or the CD4(+)8(-) DC under all conditions tested.
Dendritic cells (DC) develop in GM-CSF-stimulated cultures from murine bone marrow progenitors in serum-free (or low serum) medium. CD11c(+) myeloid DC from 7-day cultures stimulated with TNF-alpha, IFN-alpha, IFN-gamma, or LPS up-regulated surface expression of CD40 and CD86 costimulator and MHC class II molecules, did not up-regulate the low "spontaneous" release of IL-18, and did not release IFN-gamma. Stimulation of in vitro-generated DC with exogenous IL-12 and IL-18 (but not with IL-4 or LPS plus IL-18) induced IFN-gamma expression and release in 15-20% of the DC (detectable by FACS analyses or ELISA). Endogenous IL-12 p70 produced by DC in response to ligation of CD40 stimulated IFN-gamma release when exogenous IL-18 was supplied. In vivo-generated, splenic CD8alpha(+) and CD8alpha(-) DC (from immunocompetent and immunodeficient H-2(d) and H-2(b) mice) cultured with IL-12 and IL-18 released IFN-gamma. The presence of LPS during the stimulation of DC with IL-18 plus endogenous (CD40 ligation) or exogenous IL-12 did not affect their IFN-gamma release. In contrast, splenic DC pretreated in vitro or in vivo by LPS strikingly down-regulated IFN-gamma release in response to stimulation by IL-18 and (endogenous or exogenous) IL-12. Hence, DC are a source of early IFN-gamma generated in response to a cascade of cytokine- and/or cell-derived signals that can be positively and negatively regulated.
Autoimmune disease in MRL-Fas(lpr) mice is characterized by fatal nephritis, systemic pathology, and autoantibodies, mimicking human lupus. We previously reported that 1) intrarenal IL-12 elicits nephritis by fostering the accumulation of intrarenal IFN-gamma-secreting T cells, and 2) MRL-Fas(lpr) mice deficient in the IFN-gamma receptor were spared from nephritis. Therefore, we hypothesized that eliminating IL-12 in MRL-Fas(lpr) mice reduces IFN-gamma-secreting cells and thereby prevents systemic pathology. For this purpose, we constructed an IL-12p40-deficient MRL-Fas(lpr)(IL-12(-/-)) strain. We determined that glomerular and interstitial, but not perivascular, renal pathology were decreased in IL-12(-/-) mice vs the wild-type (WT) strain (5 mo of age). Similarly, systemic pathology (lung, lacrimal and salivary glands, skin, and lymphadenopathy) was diminished. The intrarenal accumulation of T cells (CD4(+), CD8(+), CD4(-)CD8(-)B220(+)) and macrophages was dramatically reduced in IL-12(-/-) MRL-Fas(lpr) kidneys. We determined that there were fewer IFN-gamma transcripts (>70%) in the IL-12(-/-) protected kidneys compared with the WT kidneys. Similarly, cells propagated from IL-12(-/-) MRL-Fas(lpr) kidneys generated substantially less IFN-gamma when stimulated with IL-12 and IL-18 compared with those from WT kidneys, and we detected fewer CD8 and B220 T cells producing IFN-gamma in these IL-12(-/-) MRL-Fas(lpr) kidneys. Of note, survival was modestly extended in the IL-12(-/-) MRL-Fas(lpr) mice. While lung and lacrimal and salivary gland pathology remained reduced in moribund IL-12(-/-) MRL-Fas(lpr) mice, renal pathology and IFN-gamma expression were equivalent to those in the WT strain. Thus, we suggest that IL-12 is a therapeutic target for multiple tissues in lupus; however blocking IL-12 alone is not sufficient to confer enduring protection from lupus nephritis.
CD11c(+) (F4/80(-) CD68(-)) dendritic cells (DC) in the colonic lamina propria (cLP) of normal and immunodeficient (RAG1(-/-)) C57BL/6 (B6) mice show high surface expression of MHC class I/II molecules and CD1d, and low surface expression of CD40, CD80, CD86 costimulator molecules. CD4(+) alpha beta T cells from normal or MHC class II-deficient B6 mice transferred into congenic RAG1(-/-) hosts induce a progressive, lethal colitis. Concomitant with colitis development, DC in the inflamed cLP increase in number and up-regulate surface expression of CD1d, MHC class II molecules and CD40, CD80, CD86 costimulator molecules. cLP DC from non-transplanted (healthy) and transplanted (diseased) mice produce similar amounts of IL-12 p70 and IL-10 in response to CD40 signaling, but the inducible IL-12 p40 release is 5-15-fold higher in mice with colitis than in non-transplanted mice. Binding of IL-12 p40 to p19 generates IL-23. Freshly isolated cLP lymphocytes (cLPL) from transplanted, diseased mice express 3-10-fold more p19 transcripts than cLPL from non-transplanted, healthy mice. p19 expression by cLPL is further up-regulated in response to CD40 ligation. Freshly isolated cLP DC from transplanted mice with colitis (but not from non-transplanted controls) stimulate IFN-gamma (but not IL-4 or IL-13) release by co-cultured NKT cells. Incolitis, DC accumulate in the cLP, show an activated surface phenotype, up-regulate IL-12 p40 and p19 expression, and 'spontaneously' stimulate NKT-like cells. cLP DC may be interesting targets for novel therapeutic approaches to modulate mucosal T cell responses in situ.
Local production of IL-17 is a significant factor in effective host defense against Gram-negative bacteria. However, the proximal events mediating IL-17 elaboration by T cells remain unclear. In this study, we show in vivo that intact Toll-like receptor 4 signaling in the lung is required for induction of both the p19 transcript of IL-23 and IL-17 protein elaboration in response to Klebsiella pneumoniae. Although IL-17 is widely considered a CD4(+) T cell product, we also demonstrate significant in vitro IL-17 production by CD8(+) T cells after culture in medium from dendritic cells exposed to these bacteria. The dominant portion of this IL-17-inducing activity for both CD4(+) and CD8(+) T cells is IL-23. These data demonstrate the critical signaling pathway for IL-17 induction in the host response to Gram-negative pulmonary infection and suggest a direct role for IL-23 in CD8(+) T cell IL-17 production.
Dendritic cells (DC) are the main orchestrators of specific immune responses. Depending on microbial information they encounter in peripheral tissues, they promote the development of Th1, Th2 or unpolarized Th cell responses. In this study we have investigated the immunomodulatory effect of non-pathogenic intestinal Gram-negative (Escherichia coli, Bacteroides vulgatus,Veillonella parvula, Pseudomonas aeruginosa) and Gram-positive (Bifidobacterium adolescentis, Enterococcus faecalis, Lactobacillus plantarum and Staphylococcus aureus) bacteria on human monocyte-derived DC (moDC). None of the Gram-positive bacteria (GpB) primed for Th1 or Th2 development. In contrast, despite the low levels of IL-12 they induce, all Gram-negative bacteria (GnB) primed moDC for enhanced Th1 cell development, which was dependent on IL-12 and an additional unidentified cofactor. Strikingly, GnB-matured moDC expressed elevated levels of p19 and p28 mRNA, the critical subunits of IL-23 and IL-27, respectively, suggesting that the IL-12 family members may jointly be responsible for their Th1-driving capacity. Purified major cell wall components of either GnB or GpB did not yield Th cell profiles identical to those obtained with whole bacteria, and could not explain the induction of the IL-12 family members nor Th1 priming by GnB. Importantly, this study gives indications that the expression of the different IL-12 family members is dictated by different priming conditions of immature DC.
Interleukin-23, a recently described cytokine produced by activated antigen-presenting cells, including dendritic cells, is a p19/p40 heterodimer. The p40 subunit is shared with IL-12, the major Th1-driving cytokine, while p19 is distantly related to IL-12 p35. IL-23 has pro-inflammatory actions, inducing IL-17 secretion from activated CD4+ T cells, and stimulating the proliferation of memory CD4+ T cells. Here, we examined the effects of PGE2, a well-known immunomodulator, on the production of IL-23 by bone marrow- derived dendritic cells (BM-DCs). Our results indicate that PGE2 increases the production of functional IL-23 from immature BM-DCs in a time- and dose-dependent manner. PGE2 induces both the expression of p19 and p40, without affecting p35 expression. The effect of PGE2 is mediated through the specific receptors EP2/4 and is mimicked by cAMP-inducing agents, such as forskolin and dbcAMP. Although PGE2 also induces IL-1beta and IL-6 expression in non-stimulated DCs, the stimulatory effect of PGE2 on IL-23 production is not mediated through IL-1beta or IL-6. GM-CSF, the pro-inflammatory cytokine required for the generation of BM-DCs, amplifies the IL-23 inducing activity of PGE2 in a synergistic manner. Recent studies described both pro- and anti-inflammatory effects of PGE2, and our results suggest an additional mechanism for its pro-inflammatory role, particularly significant for autoimmune diseases, such as rheumatoid arthritis.
To investigate the role of Interleukin-17 (IL-17), Interferon-gamma (IFN-gamma), and macrophage inflammatory protein-3 alpha (MIP-3alpha) in the pathogenesis of psoriasis, reverse transcriptase-polymerase chain reaction (RT-PCR) was used to semi-quantitatively analyze the mRNA expression of IL-17, IFN-gamma, and MIP-3alpha in 31 psoriatic lesions and 16 normal skin tissues. The results showed that the mRNA of the three cytokines was present in all specimens. And the expression level of IL-17 mRNA in skin lesions was 1.1416 +/- 0.0591, which was significantly higher than that in normal controls (0.8788 +/- 0.0344, P<0.001). The expression levels of IFN-gamma mRNA were 1.1142 +/- 0.0561 and 0. 9050 +/- 0.0263, respectively, with significant difference (P<0.001). And the expression levels of MIP-3alpha mRNA in psoriatic lesions was 1.1397 +/- 0.0521, which was markedly higher than that in normal controls (0.8681 +/- 0.0308, P<0.001). These findings indicate that up-regulated expression of IL-17, IFN-gamma, and MIP-3alpha might be involved in the pathogenesis of psoriasis.
IL-17A was cloned more than 10 years ago and six IL-17 family members (IL-17A-F) have subsequently been described. IL-17A is largely produced by activated memory T lymphocytes but stimulates innate immunity and host defense. IL-17A and IL-17F both mobilize neutrophils partly through granulopoeisis and CXC chemokine induction, as well as increased survival locally. IL-17A and IL-17F production by T lymphocytes is regulated by IL-23 independent of T cell receptor activation. Increasing evidence shows that IL-17 family members play an active role in inflammatory diseases, autoimmune diseases, and cancer. This places IL-17 family members and their receptors as potential targets for future pharmacotherapy.
The potential therapeutic activity of a human monoclonal antibody to the human interleukin-12 p40 subunit (anti-IL-12p40) has been established both in vitro and in vivo, warranting a first-in-human investigation in psoriasis. This phase I, first-in-human, non-randomized, open-label study evaluated the short-term safety, pharmacokinetics, and clinical response of single, ascending, intravenous (IV) doses of anti-IL-12p40 in subjects with moderate-to-severe psoriasis vulgaris. Eighteen subjects with at least 3% body surface area involvement were enrolled in four dose groups (0.1, 0.3, 1.0, and 5.0 mg per kg). Safety, pharmacokinetics, and clinical response (e.g., Psoriasis Area and Severity Index (PASI)) were monitored at baseline and at specific time points over a 16-wk follow-up period. Anti-IL-12p40 was generally well tolerated. No related serious adverse events or infusion reactions were reported, and most adverse events were mild. IV anti-IL-12p40 yielded linear pharmacokinetics, with a mean terminal half-life of approximately 24 d. Dose-dependent associations with both the rate and extent of clinical response were observed across the four dose groups. Twelve of 18 subjects (67%) achieved at least a 75% improvement in PASI between 8 and 16 wk after study agent administration. Significant and sustained concentration-dependent improvements in psoriatic lesions were observed in most subjects.