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Positive regulation of T-cell responses by PGE2. PGE2 has diverse pro-inflammatory effects on T cells. (a) Nanomolar physiological concentrations of PGE2 induce phosphatidylinositol 3 kinase (PI3K)/Akt signalling pathways through the EP4 receptor that serve to promote Th1 differentiation patterns. (b) PGE2 has also been shown to potentiate Th17 differentiation through EP2-cAMP-PKA signalling pathways, primarily through (c) induction of IL-1β and IL-23 receptor (d) PGE2 has been demonstrated to induce co-stimulatory molecules on the surface of DCs, thereby promoting T-cell proliferation. It has also been shown to promote secretion of specific cytokines by DCs, for example, IL-12, which further directs Th1 differentiation and IL-23, which enhances Th17 polarization.
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Our understanding of the key players involved in the differential regulation of T-cell responses during inflammation, infection and auto-immunity is fundamental for designing efficient therapeutic strategies against immune diseases. With respect to this, the inhibitory role of the lipid mediator prostaglandin E(2) (PGE(2)) in T-cell immunity has be...
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... This study also shows that PGE 2 -matured DCs upregulate the expression of OX-40L, OX-40 and CD70 on the surface of T cells, enlisting a possible role in T-cell-T-cell interactions and sustained antigen- specific immune responses. 28 A comprehensive summary of the pro-inflammatory role of PGE 2 in T-cell response is shown in Figure 3. immunodeficiency virus and parasitic infections. ...Citations
... PGE2 inhibits signalling via T cell receptors, potentially contributing to the resolution of inflammation. Furthermore, PGE2 restricts the immune response by blocking Blymphocyte differentiation and impairing their capacity to present antigens [53]. TGF-βdeficient mice models have shown reduced proliferation of T cells through several mechanisms, including modulation of the mechanistic target of rapamycin (mTOR) and Forkhead box O3 (FOXO3) [54]. ...
Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma worldwide, constituting around 30–40% of all cases. Almost 60% of patients develop relapse of refractory DLBCL. Among the reasons for the therapy failure, tumour microenvironment (TME) components could be involved, including tumour-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), tumour-associated neutrophils (TANs), cancer-associated fibroblasts (CAFs), and different subtypes of cytotoxic CD8+ cells and T regulatory cells, which show complex interactions with tumour cells. Understanding of the TME can provide new therapeutic options for patients with DLBCL and improve their prognosis and overall survival. This review provides essentials of the latest understanding of tumour microenvironment elements and discusses their role in tumour progression and immune suppression mechanisms which result in poor prognosis for patients with DLBCL. In addition, we point out important markers for the diagnostic purposes and highlight novel therapeutic targets.
... Research indicates that prostaglandin E2 (PGE2) not only inhibits the activity and proliferation of CD4+ and CD8+ T cells by promoting the expression of co-inhibitory molecules PD-1 and TIM-3 on T cells (207)(208)(209), but also regulates the differentiation and activation of Th17 cells through prostaglandin receptor EP2-and EP4-mediated signaling, cAMP pathways, and by inhibiting the function of transcription factor IRF4 (208,210). PGE2, through its dual regulation of DCs and T cells, not only reduces the production of inflammatory mediators but also decreases T cell-mediated inflammatory responses, thereby helping to maintain immune homeostasis and prevent the overactivation of autoimmune responses. ...
Efferocytosis, the process of engulfing and removing apoptotic cells, plays an essential role in preserving tissue health and averting undue inflammation. While macrophages are primarily known for this task, dendritic cells (DCs) also play a significant role. This review delves into the unique contributions of various DC subsets to efferocytosis, highlighting the distinctions in how DCs and macrophages recognize and handle apoptotic cells. It further explores how efferocytosis influences DC maturation, thereby affecting immune tolerance. This underscores the pivotal role of DCs in orchestrating immune responses and sustaining immune equilibrium, providing new insights into their function in immune regulation.
... CD74 is the invariant chain of major histocompatibility complex II (MHC-II). Extracellular binding of MIF induces heterodimerization with CD44 and subsequent ERK-MAPK pathway activation, resulting in, amongst others, prostaglandin E2 (PGE2) production, a well-known suppressor of T cell activation 53,78 . Others showed that MIF can cause activation-induced T cell death through the IFN-γ pathway 79 . ...
While chimeric antigen receptor (CAR) T-cell therapies are showing highly promising first results in neuroblastoma, immunosuppressive tumor microenvironments (TME) limit T cell persistence and durable clinical efficacy. To improve CAR T-cell efficacy further, we applied a multi-omics approach including single-cell RNA sequencing and proteomics, which identified 13 targetable immunosuppressive factors in neuroblastoma. Of these, macrophage migration inhibitory factor (MIF) and midkine (MDK) were validated across multiple published RNA datasets. Moreover, they were secreted in high abundance by neuroblastoma tumoroids. Functional validation experiments revealed MIF as a potent inhibitor of CAR T-cells, in vitro and in vivo. Degradation of MIF by PROTAC technology significantly enhanced CAR T-cell activation targeting GPC2 and B7-H3, providing a potential intervention against MIF. By defining the immunosuppressive effects of neuroblastoma’s TME on CAR T-cell efficacy, particularly the pivotal role of MIF, we provide a therapeutic strategy for improving adoptive cell therapies for this pediatric malignancy.
... Tuft cells secrete diverse effector molecules with immunomodulatory functions, such as IL-25, PGs, and LTs (1). LTs and PGs, in particular, can suppress T cell activity (58,59). Allergic airway tuft cells were recently shown to be capable of producing prostaglandin E2, which has documented roles in driving T cell dysfunction in LCMV infection and cancer by impairing CD8 + T cell cytotoxicity, proliferation, and survival (60)(61)(62). ...
The persistent murine norovirus strain MNV CR6 is a model for human norovirus and enteric viral persistence. MNV CR6 causes chronic infection by directly infecting intestinal tuft cells, rare chemosensory epithelial cells. Although MNV CR6 induces functional MNV-specific CD8 ⁺ T cells, these lymphocytes fail to clear infection. To examine how tuft cells promote immune escape, we interrogated tuft cell interactions with CD8 ⁺ T cells by adoptively transferring JEDI (just EGFP death inducing) CD8 ⁺ T cells into Gfi1b-GFP tuft cell reporter mice. Unexpectedly, some intestinal tuft cells partially resisted JEDI CD8 ⁺ T cell–mediated killing—unlike Lgr5 ⁺ intestinal stem cells and extraintestinal tuft cells—despite seemingly normal antigen presentation. When targeting intestinal tuft cells, JEDI CD8 ⁺ T cells predominantly adopted a T resident memory phenotype with decreased effector and cytotoxic capacity, enabling tuft cell survival. JEDI CD8 ⁺ T cells neither cleared nor prevented MNV CR6 infection in the colon, the site of viral persistence, despite targeting a virus-independent antigen. Ultimately, we show that intestinal tuft cells are relatively resistant to CD8 ⁺ T cells independent of norovirus infection, representing an immune-privileged niche that can be leveraged by enteric microbes.
... However, vitamin E may be able to have an inhibitory effect on the release of inflammatory mediators. Prostaglandin E 2 (PGE 2 ) is an important proinflammatory mediator, and its synthesis rate is mainly controlled by cyclooxygenase (COX)-1 and COX-2 [80]. COX-1 is responsible for maintaining the normal level of prostaglandin in the body, but COX-2 can be activated by the proinflammatory mediator, resulting in excessive synthesis of PGE 2 at the injured site, thus causing a more serious in-flammatory injury [81]. ...
Inflammatory bowel disease (IBD) includes ulcerative colitis and Crohn’s disease, and it is a multifactorial disease of the intestinal mucosa. Oxidative stress damage and inflammation are major risk factors for IBD. Vitamin E has powerful antioxidant and anti-inflammatory effects. Our previous work and other investigations have shown that vitamin E has a positive effect on the prevention and treatment of IBD. In this paper, the source and structure of vitamin E and the potential mechanism of vitamin E’s role in IBD were summarized, and we also analyzed the status of vitamin E deficiency in patients with IBD and the effect of vitamin E supplementation on IBD. The potential mechanisms by which vitamin E plays a role in the prevention and treatment of IBD include improvement of oxidative damage, enhancement of immunity, maintenance of intestinal barrier integrity, and suppression of inflammatory cytokines, modulating the gut microbiota and other relevant factors. The review will improve our understanding of the complex mechanism by which vitamin E inhibits IBD, and it also provides references for doctors in clinical practice and researchers in this field.
... As shown in Supplementary Figure S3 In our previous analysis, we found in 18 of 34 subjects a >25% increase in the primary study parameter, serum prostaglandin E 2 (PGE 2 ), upon nasturtium intervention (verum), while it was decreased by >25% in 9 subjects [19]. PGE 2 is a multifunctional molecule that orchestrates a wide range of biological responses such as tissue homeostasis and inflammation, and it is one of the most abundant prostanoids in the human body [38,39]. We thus used the same subgroups of participants here to further investigate whether these large variations in PGE 2 response upon nasturtium intervention are associated with a particular change in the composition of the gut microbiome, as previously proposed [40], or serum metabolome. ...
Despite substantial heterogeneity of studies, there is evidence that antibiotics commonly used in primary care influence the composition of the gastrointestinal microbiota in terms of changing their composition and/or diversity. Benzyl isothiocyanate (BITC) from the food and medicinal plant nasturtium (Tropaeolum majus) is known for its antimicrobial activity and is used for the treatment of infections of the draining urinary tract and upper respiratory tract. Against this background, we raised the question of whether a 14 d nasturtium intervention (3 g daily, N = 30 healthy females) could also impact the normal gut microbiota composition. Spot urinary BITC excretion highly correlated with a weak but significant antibacterial effect against Escherichia coli. A significant increase in human beta defensin 1 as a parameter for host defense was seen in urine and exhaled breath condensate (EBC) upon verum intervention. Pre-to-post analysis revealed that mean gut microbiome composition did not significantly differ between groups, nor did the circulating serum metabolome. On an individual level, some large changes were observed between sampling points, however. Explorative Spearman rank correlation analysis in subgroups revealed associations between gut microbiota and the circulating metabolome, as well as between changes in blood markers and bacterial gut species.
... As given in Supplementary Figure S3 In our previous analysis, we found in 18 of 34 subjects a >25% increase in the primary study parameter, serum prostaglandin E2 (PGE2), upon nasturtium intervention (verum), while it was >25% decreased in nine subjects [19]. PGE2 is a multifunctional molecule that orchestrates a wide range of biological responses like tissue homeostasis and inflammation and it is one of the most abundant prostanoids in the human body [37,38]. We thus used the same subgroups of participants here for further investigating whether these large variations in PGE2 response upon nasturtium intervention are associated with a particular change in the composition of the gut microbiome, as previously proposed [39], or serum metabolome. ...
Despite substantial heterogeneity of studies, there is evidence that antibiotics commonly used in primary care influence the composition of the gastrointestinal microbiota in terms of changing the composition and/or diversity. Benzyl isothiocyanate (BITC) from the food and medicinal plant nasturtium (Tropaeolum majus) is known for its antimicrobial activity and is used for the treatment against infections of the draining urinary tract and upper respiratory tract. Against this background, we raised the question whether 14 d nasturtium intervention (3 g daily, N=30 healthy females) could also impact the normal gut microbiota composition. Spot urinary BITC excretion highly correlated with a weak, but significant antibacterial effect against Escherichia coli. A significant increase in human beta defensin 1 as parameter for host defense was seen in urine and exhaled breath condensate (EBC) upon verum intervention. Pre-to-post analysis revealed that mean gut microbiome composition did not significantly differ between groups, nor did circulating serum metabolome. On an individual level, partly large changes were observed between sampling points, though. Explorative Spearman rank correlation analysis in subgroups revealed associations between gut microbiota and the circulating metabolome, as well as between changes in blood markers and bacterial gut species.
... The top 5 differentially expressed genes (DEGs) were both indicated on a volcano plot ( Fig 5A) and shown in Table 1. The gene encoding prostaglandin-endoperoxide synthase 2 (PTGS2), also known as cyclooxygenase-2 (COX-2), emerged as a compelling target for further investigation because its PGE2 product has been previously shown to reduce T cell proliferation and promote the activation of Tregs [24], observations that are consistent with our findings in MoDCs-P. Therefore, the PTGS2 gene was selected for validation of its expression level using relative RT-qPCR. ...
Leptospirosis is a global zoonosis caused by pathogenic Leptospira . The disease outcome is influenced by the interplay between innate and adaptive immune responses. Dendritic cells (DCs) play a crucial role in shaping the adaptive immune response. A recent study revealed that pathogenic Leptospira limited the activation of human monocyte-derived dendritic cells (MoDCs) compared to non-pathogenic Leptospira , but their impact on T-cell responses has not been investigated. Our study is the first to explore how viable pathogenic and non-pathogenic Leptospira affect the interaction between human MoDCs and T cells. We found that MoDCs infected with pathogenic leptospires ( L . interrogans serovar Pomona and a clinical isolate, MoDCs-P) exhibited lower levels of CD80 and CD83 expression, suggesting partially impaired MoDC maturation, induced regulatory T cells (Tregs) while failing to induce CD4 ⁺ T cell proliferation, compared to MoDCs infected with non-pathogenic leptospires ( L . biflexa serovar Patoc and L . meyeri serovar Ranarum, MoDCs-NP). In contrast, non-pathogenic leptospires enhanced MoDC maturation and induced higher T cell proliferation including IFN-γ-producing CD4 ⁺ T cells, indicative of a Th1-type response. Furthermore, pathogenic leptospires induced higher MoDC apoptosis through a cysteine aspartic acid-specific protease-3 (caspase-3)-dependent pathway and upregulated expression of the prostaglandin-endoperoxide synthase 2 ( PTGS2 ) gene. Notably, prostaglandin E2 (PGE2), a product of the PTGS2 pathway, was found at higher levels in the sera of patients with acute leptospirosis and in the supernatant of MoDCs-P, possibly contributing to Treg induction, compared to those of healthy donors and MoDCs-NP, respectively. In conclusion, this study reveals a novel immunosuppressive strategy employed by pathogenic Leptospira to evade host immunity by partially impairing MoDC maturation and inducing Tregs. These findings deepen our understanding of leptospirosis pathogenesis in humans and may provide a novel strategy to modulate DCs for the prevention and treatment of the disease.
... PD-L1 affects CD4 + T cell proliferation mainly by inducing their apoptosis through the PD-1 receptor on their surface [38,39]. PTGS-2 gene codes PGE-2 protein, which is also a well-known inhibitor of CD4 + T cell proliferation and differentiation [40,41]. The gene expression of PD-L1, another factor involved in the immunomodulatory ability of MSCs, was also affected by osteogenic differentiation. ...
The differentiation ability of human periodontal ligament mesenchymal stromal cells (hPDL-MSCs) in vivo is limited; therefore, some studies considered strategies involving their pre-differentiation in vitro. However, it is not known how the differentiation of hPDL-MSCs influences their immunomodulatory properties. This study investigated how osteogenic differentiation of hPDL-MSCs affects their ability to suppress CD4+ T-lymphocyte proliferation. hPDL-MSCs were cultured for 21 days in osteogenic differentiation or standard culture media. Allogeneic CD4+ T lymphocytes were co-cultured with undifferentiated and differentiated cells in the presence or absence of interferon (IFN)-γ, interleukin (IL)-1β or tumor necrosis factor (TNF)-α, and their proliferation and apoptosis were measured. Additionally, the effects of these cytokines on the expression of immunomodulatory or pro-inflammatory factors were investigated. Our data show that osteogenic differentiation of hPDL-MSCs reduced their ability to suppress the proliferation of CD4+ T lymphocytes in the presence of IFN-γ and enhanced this ability in the presence of IL-1β. These changes were accompanied by a slightly decreased proportion of apoptotic CD4+ in the presence of IFN-γ. The osteogenic differentiation was accompanied by decreases and increases in the activity of indoleamine-2,3-dioxygenase in the presence of IFN-γ and IL-1β, respectively. The basal production of interleukin-8 by hPDL-MSCs was substantially increased upon osteogenic differentiation. In conclusion, this study suggests that pre-differentiation strategies in vitro may impact the immunomodulatory properties of hPDL-MSCs and subsequently affect their therapeutic effectiveness in vivo. These findings provide important insights for the development of MSC-based therapies.
... Speci cally, MMPs are known to be factors that suppress brosis. In addition, since TSG-6 and IL-10 are immune regulatory genes, we speculate that these genes may play an inhibitory role against brosis caused by overactive immune responses via the induction of pro-in ammatory cytokines [18][19][20][21][22] . ...
Pulmonary fibrosis is a progressive disease caused by interstitial inflammation. Treatments are extremely scarce; therapeutic drugs and transplantation therapies are not widely available due to cost and a lack of donors, respectively. Recently, there has been a high interest in regenerative medicine and exponential advancements in stem cell-based therapies have occurred. However, a sensitive imaging technique for investigating the in vivo dynamics of transplanted stem cells has not yet been established and the mechanisms of stem cell-based therapy remain largely unexplored.
In this study, we administered adipose tissue-derived mesenchymal stem cells (ASCs) labeled with quantum dots (QDs; 8.0 nM) to a mouse model of bleomycin-induced pulmonary fibrosis in an effort to clarify the relationship between in vivo dynamics and therapeutic efficacy. These QD-labeled ASCs were injected into the trachea of C57BL/6 mice seven days after bleomycin administration to induce fibrosis in the lungs. The therapeutic effects and efficacy were evaluated via in vivo/ex vivo imaging, CT imaging, and H&E staining of lung sections.
The QD-labeled ASCs remained in the lungs longer and suppressed fibrosis. The 3D imaging results showed that the transplanted cells accumulated in the peripheral and fibrotic regions of the lungs. These results indicate that ASCs may play a significant role in the therapeutic effects of pulmonary fibrosis. Thus, QD labeling could be a suitable and sensitive imaging technique for evaluating in vivo kinetics in correlation with the efficacy of cell therapy.
