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IL-6 classic- signaling and IL-6 trans-signaling. IL-6 Classic-signaling requires membrane bound IL-6R and is restricted to hepatocytes, some epithelial cells and some leukocytes. IL-6 trans-signaling requires sIL-6R and is possible on all cells of the body since all cells express the gp130 protein.
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Interleukin-6 (IL-6) is a cytokine with many activities. It has functions in the regulation of the immune system and the nervous system. Furthermore, IL-6 is involved in liver regeneration and in the metabolic control of the body. On target cells, IL-6 binds to an 80 kDa IL-6 receptor (IL-6R). The complex of IL-6 and IL-6R associates with a second...
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Interleukin-6 (IL-6) is a multifunctional cytokine with important functions in various physiologic processes. Mice lacking IL-6 exhibit multiple phenotypic abnormalities such as an inadequate immune and acute-phase response, and elevated levels of circulating IL-6 have been found to accompany several pathologic conditions. IL-6 binds the non-signal...
Objective:
To study the role of B lymphocytes in systemic sclerosis (SSc).
Patients and methods:
Peripheral B cell subpopulations, interleukin 6 (IL-6) and transforming growth factor-beta (TGF-β) productions were analyzed using flow cytometry and multiplex assay. Fibroblasts proliferation rate upon incubation with supernatants of B cells isolate...
Background
Interleukin-6 (IL-6) is released from skeletal muscle during exercise and systemic IL-6 levels therefore increase acutely in response to a single bout of exercise. We recently showed that an acute increase in IL-6 delayed gastric emptying rate and improved postprandial glycemia. Here we investigate whether repeated increases in IL-6, ind...
Interleukin-6 (IL-6) signaling plays an important proinflammatory role, but this role is restricted by regulatory mechanisms that, for example, reduce the cell surface availability of the signal-transducing chain of the IL-6 receptor, gp130. The aim of this study was to determine whether the inflammatory environment in arthritic joints has an impac...
Signaling of the cytokine interleukin-6 (IL-6) via its soluble IL-6 receptor (sIL-6R) is responsible for the proinflammatory properties of IL-6 and constitutes an attractive therapeutic target, but how the sIL-6R is generated in vivo remains largely unclear. Here, we use liquid chromatography–mass spectrometry to identify an sIL-6R form in human se...
Citations
... IL-6 binding to mIL-6R results in a complex that recruits glycoprotein (gp)130 to activate intracellular signalling [17]. gp130 dimerization activates Janus kinase (JAK), a tyrosine receptor kinase, which phosphorylates tyrosine residues on gp130 to recruit and phosphorylate signal transducers and STAT3 [17]. ...
... IL-6 binding to mIL-6R results in a complex that recruits glycoprotein (gp)130 to activate intracellular signalling [17]. gp130 dimerization activates Janus kinase (JAK), a tyrosine receptor kinase, which phosphorylates tyrosine residues on gp130 to recruit and phosphorylate signal transducers and STAT3 [17]. Phosphorylated STAT3 then relocates into the nucleus where it regulates transcription and expression of target genes, activating a variety of immune responses [18]. ...
Tocilizumab is an immunoglobulin G1 monoclonal antibody targeting the interleukin-6 receptor (IL-6R). BAT1806/BIIB800 (tocilizumab-bavi) has been developed as a biosimilar to the reference product tocilizumab (TCZ). The objective of this study was to demonstrate physicochemical and functional similarity between BAT1806/BIIB800 and TCZ in a comprehensive comparability exercise.
A comprehensive panel of over 20 methods was used to generate datasets comparing critical and non-critical product quality attributes for 10 BAT1806/BIIB800 lots and 44 TCZ lots (16 sourced from China, 16 from the EU, and 12 from the US). Primary structure, higher-order structure, and physicochemical properties were assessed using liquid chromatography, mass spectrometry, various spectroscopy techniques/methods, capillary electrophoresis, and thermoanalytical techniques. Fragment antigen-binding (Fab)- and fragment crystallizable (Fc)-mediated biological properties were assessed using cell-based assays, immunoassays, flow cytometry, and kinetic binding assays.
BAT1806/BIIB800 and TCZ (irrespective of source) were shown to be similar in terms of structural and functional properties. No differences were observed in terms of the most critical quality attributes, that is, soluble-IL-6R binding and inhibition of IL-6-mediated cell proliferation. BAT1806/BIIB800 and TCZ demonstrated similarity in terms of Fab- and Fc-mediated binding and biological activity. Minor differences were observed in glycosylation (afucosylation and sialylation), glycation, aggregation, and charge variants, which were demonstrated to be not clinically relevant.
BAT1806/BIIB800 and TCZ were highly similar for all critical quality attributes. Where differences were observed in less critical quality attributes, additional analytical assessments and clinical study results determined these to be not clinically meaningful.
... [16,20] Importantly, IL-6 initially binds to the IL-6 receptor (IL-6R), forming a complex that activates cells via glycoprotein 130 (gp130), thus mediating the biological activities of the IL-6 cytokine. [21] IL-6R exists in both a transmembrane form found on the cell surface and in a soluble form (sIL-6R). [22] The non-synonymous variant rs2221845 in exon 9 of the IL-6R causes an asparagine to alanine substitution at position 358 (Asp358Ala) within the IL-6R proteolytic cleavage site. [23] It has been associated with the risk of various common diseases characterized by a significant inflammatory component. ...
Interleukin-6 (IL-6), a pro-inflammatory cytokine, is an important regulator of the inflammatory immune response. We aimed to assess the association of common single nucleotide polymorphisms (SNPs) in IL-6 (rs1800795 G > C, rs1800797 A > G) and interleukin-6 receptor (IL-6R) (rs2228145 A > C) genes with HIV-1 infection, AIDS progression, and response to treatment. In this case-control study involving 199 individuals living with HIV-1 and 200 HIV-uninfected controls, we conducted genotyping of IL-6/IL-6R SNPs using TaqMan real-time PCR assays. Soluble IL-6 levels were measured using ELISA. No associations were found between the investigated SNPs and HIV infection. However, a significant association was noted between the C-G and G-A haplotypes and susceptibility to HIV-1 infection. Additionally, a significant association was revealed between HIV-1 RNA viral loads and IL-6 SNP G > C in the post-treatment HIV group. Interestingly, we observed a significant association between the investigated SNPs and protection against progression to AIDS, namely the IL-6 G > A SNP in its recessive model and the IL-6R A > C SNP in its codominant and dominant models. Nevertheless, we found no significant differences between IL-6 levels and the different genotypes and alleles of the IL-6 gene either before or after combination antiretroviral therapy. IL-6 promoter haplotypes are associated with susceptibility to HIV-1 infection. Furthermore, IL-6 A > G and IL-6R A > C polymorphisms have been associated with protection against AIDS progression. Interestingly, the IL-6 G > C SNP may affect the response to treatment in people living with HIV-1.
... Blood samples were used to analyze the levels of anti-inflammatory cytokines interleukin 10 (IL-10) and transforming growth factor beta (TGF-β1), which have been connected to a lower risk of several immunemediated diseases (Burmeister & Marriott, 2018;Li et al., 2006;Opal & DePalo, 2000;Prud'homme and Piccirillo, 2000); proinflammatory cytokines interleukin 17A (IL-17A), interleukin 1 beta (IL-1β), and tumor necrosis factor (TNF-α), which have been associated with the risk of immune-mediated diseases (Dinarello, 2000;Honkanen et al., 2010;Kuwabara et al., 2017); and multifunctional cytokines interleukin 6 (IL-6) and interleukin 21 (IL-21), which have both anti-inflammatory and proinflammatory properties (Mehta et al., 2004;Rose-John, 2012). ...
... In this investigation, we used species C Ads [16] to study the role of macrophages expressing or lacking MARCO in Ad-induced hypersensitization to LPS, specifically in the LPS-induced TNFα, IL-6, IL-10, and IFN-αβ responses of naïve and Adinfected mice. The R-LPS of S. minnesota R595 was used, which allows the evaluation of the role of CD14 in the production of the unambiguously pro-inflammatory TNF-α [26], the anti-inflammatory IL-10 [27], and IL-6 and IFN-αβ, which, depending on the context, have pro-or anti-inflammatory properties [28][29][30]. Experiments with in vitro-generated Max-Planck-Institute (MPI) cells, AM-like non-transformed macrophage lines [31], bone marrow-derived macrophages (BMM), and freshly isolated AM and peritoneal macrophages (PM) exposed either to Ad or recombinant IFN-β suggest that in Ad-infected mice, not all macrophage populations contribute to the enhanced TNF-α and IL-6 overresponse. We also show that the IFN-αβ-mediated proinflammatory response, i.e., enhanced TNF-α and IL-6, but not IL-10 response, is inducible in human blood samples exposed to adenovirus-based SARS-CoV-2 vaccines or human recombinant (hr)IFN-β. ...
In mice, adenovirus (Ad)-elicited IFN-ab mediates the overproduction of LPS stimulated cytokines such as TNFa and IL-6. We found that Ad infection also mediates the overproduction of IFN-ab itself and enables its production in splenic marginal zone macrophages, which don’t produce IFN-ab in response to LPS alone. We show the importance of the scavenger receptor MARCO for Ad uptake and cytokine overproduction in vivo, and the differential contribution of infection and rIFN-b to LPS-induced cytokine response in macrophage subsets. TNF-a and IL-6 responses are enhanced in alveolar macrophages and alveolar macrophage-like lines, but downregulated in bone-marrow-derived and peritoneal macrophages, which correlates with the absence and presence of the anti-inflammatory IL-10 response. The IFN-ab response to LPS is enhanced in all four macrophage types. In Ad-infected mice, the rough LPS chemotype-induced TNF-a production partially depends on the LPS co-receptor CD14, while the IL-10 response is independent of CD14. The IFN-ab responses are strictly CD14-dependent, and partly IRF-3-independent. Upregulated TNF-a and IL-6, and downregulated IL-10 responses to LPS were also found in human blood treated ex vivo with SARS-CoV-2 adenovirus vaccine or rIFN-b. The altered reactivity of cytokine-producing cells to the ubiquitously present LPS could promote adverse effects of viral infection or vaccination.
... Sgp130Fc-mediated blockade of IL-6 trans-signaling ameliorates the inflammatory response associated with IL-6/sIL-6R/gp130 complex on target cells [207]. Tocilizumab blocks both IL-6 classical signaling and IL-6 trans-signaling, whereas Sgp130Fc is an inhibitor of only IL-6 trans-signaling (Table 3) [208]. The blockade of IL-6 can ameliorate the immune and pathophysiological role of IL-6 in type 2 allergic immune responses [15]. ...
... Blocks IL-6R [205] Olamkicept IL-6 Blocks IL-6 trans-signaling [208]. ...
Allergic conjunctivitis is one of the common immune hypersensitivity disorders that affect the ocular system. The clinical manifestations of this condition exhibit variability contingent upon environmental factors, seasonal dynamics, and genetic predisposition. While our comprehension of the pathophysiological engagement of immune and nonimmune cells in the conjunctiva has progressed, the same cannot be asserted for the cytokines mediating this inflammatory cascade. In this review, we proffer a comprehensive description of interleukins 4 (IL-4), IL-5, IL-6, IL-9, IL-13, IL-25, IL-31, and IL-33, as well as thymic stromal lymphopoietin (TSLP), elucidating their pathophysiological roles in mediating the allergic immune responses on the ocular surface. Delving into the nuanced functions of these cytokines holds promise for the exploration of innovative therapeutic modalities aimed at managing allergic conjunctivitis.
... The exact mechanism of action by which Ibuprofen may act as an ergogenic aid remains unknown, but it has been suggested that there is protection against the overproduction of pro-inflammatory cytokines, which in turn may alter the neuronal functions related to exercise-induced fatigue (Lima et al. 2015). Although speculative, changes in the inflammatory cascade due to Ibuprofen may result in the inhibition of transsignalling of IL-6 to neuronal areas through sgp130, which blocks the sIL-6R/IL-6 complex from signalling through a membrane-bound gp130 (Rose-John 2012). It follows that Ibuprofen may attenuate the fatiguing effects of endurance exercise and could improve exercise performance during heat stress. ...
The present study tested the hypothesis that ingesting 800 mg Ibuprofen prior to self-paced cycling at a fixed rating of perceived exertion (RPE) improves performance by attenuating the release of Interleukin (IL)-6 and its signalling molecules, whilst simultaneously modulating cortical activity and cerebral oxygenation to the brain. Eight healthy, recreationally active males ingested 800 mg Ibuprofen or a placebo ~ 1 h prior to performing fixed RPE cycling for 60 min in 35 °C and 60% relative humidity at an intensity of hard to very hard (RPE = 16) with intermittent maximal (RPE = 20) sprints every 10 min. Power output (PO), core and mean skin temperatures (Tc, Tsk), respectively, and heart rate (HR) were measured continuously. Electroencephalography (EEG) recordings at the frontal (Fz), motor (Cz) and Parietal (Pz) areas (90 s) were collected every 5 min. IL-6, soluble glycoprotein receptor (sgp130) and IL-6 receptor (R) were collected at pre-, 30 min and immediately post-exercise. Mean PO, HR, Tc and Tsk, and RPE were not different between trials (P ≥ 0.33). At end-exercise, the change in IL-6, sgp130 and sIL-6R was not different between trials (P ≥ 0.12). The increase in α and β activity did not differ in any cortices between trials (P ≥ 0.07); however, there was a significant reduction in α/β activity in the Ibuprofen compared to placebo trials at all sites (P ≤ 0.05). Ingesting a maximal, over-the-counter dose of Ibuprofen prior to exercise in the heat does not attenuate the release of IL-6, nor improve performance, but may influence cortical activity evidenced by a greater reduction in α/β activity.
... This could enhance the concentration of IL-6 in the bloodstream due to an increase in gut permeability. IL-6 binds to the IL-6R and regulates various functions by activating IL-6 trans-signaling in the skin [35]. It can initiate the development of Th2 cells from Th0 cells [36], and IL-6 trans-signaling is known to promote Th2-mediated AD [37]. ...
Emerging evidence suggests a link between atopic dermatitis (AD) and gastrointestinal disorders, particularly in relation to gut microbial dysbiosis. This study explored the potential exacerbation of AD by gut inflammation and microbial imbalances using an irritable bowel syndrome (IBS) mouse model. Chronic gut inflammation was induced in the model by intrarectal injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS), followed by a 4-week development period. We noted significant upregulation of proinflammatory cytokines in the colon and evident gut microbial dysbiosis in the IBS mice. Additionally, these mice exhibited impaired gut barrier function, increased permeability, and elevated systemic inflammation markers such as IL-6 and LPS. A subsequent MC903 challenge on the right cheek lasting for 7 days revealed more severe AD symptoms in IBS mice compared to controls. Further, fecal microbial transplantation (FMT) from IBS mice resulted in aggravated AD symptoms, a result similarly observed with FMT from an IBS patient. Notably, an increased abundance of Alistipes in the feces of IBS mice correlated with heightened systemic and localized inflammation in both the gut and skin. These findings collectively indicate that chronic gut inflammation and microbial dysbiosis in IBS are critical factors exacerbating AD, highlighting the integral relationship between gut and skin health.
... The activation of the IL-6 signaling cascade is initiated by binding to two types of receptors: the membrane-bound and the soluble receptor. The "trans" signaling, involves the binding of IL-6 with the soluble receptor, while "classical" signaling involves the binding of IL-6 with the membrane-bound receptor [13,14]. Ultimately, both receptors utilize the gp130 receptor subunit to initiate signaling cascades. ...
Given the increasing effectiveness of immune-based therapies, management of their associated toxicities is of utmost importance. Cytokine release syndrome (CRS), characterized by elevated levels of cytokine, poses a significant challenge following the administration of antibodies and CAR-T cell therapies. CRS also contributes to multiple organ dysfunction in severe viral infections, notably in COVID-19. Given the pivotal role of IL-6 cytokine in initiating CRS, it has been considered a most potential therapeutic target to mitigate hyperactivated immune responses. While monoclonal antibodies of IL-6 show promise in mitigating cytokine storm, concerns about immunotoxicity persist, and small molecule IL-6 antagonists remain unavailable. The present study employed sophisticated computational techniques to identify potential hit compounds as IL-6 inhibitors, with the aim of inhibiting IL-6/IL-6R protein–protein interactions. Through ligand-based pharmacophore mapping and shape similarity in combination with docking-based screening, we identified nine hit compounds with diverse chemical scaffolds as potential binders of IL-6. Further, the MD simulation of 300 ns of five virtual hits in a complex with IL-6 was employed to study the dynamic behavior. To provide a more precise prediction, binding free energy was also estimated. The identified compounds persistently interacted with the residues lining the binding site of the IL-6 protein. These compounds displayed low binding energy during MMPBSA calculations, substantiating their strong association with IL-6. This study suggests promising scaffolds as potential inhibitors of IL-6/IL-6R protein–protein interactions and provides direction for lead optimization.
Graphical abstract
... The cells lacking transmembrane IL-6R are not responsive to IL-6; however, they respond to IL-6 in the presence of sIL-6R. Thus, the IL-6 + sIL-6R complex binds to transmembrane gp130 on the cells that do not express transmembrane IL-6R, and this process is known as IL-6 trans-signaling [4]. Nowadays, sIL-6R is considered as an agonist molecule, allowing IL-6 to have an effect on the cells lacking IL-6R but ubiquitously expressing transmembrane gp130 [5]. ...
Plasma concentrations of a pleiotropic cytokine, interleukin (IL)-6, are increased in patients with cardiac myxoma. We investigated the regulation of IL-6 in cardiac myxoma. Immunohistochemical staining and reverse transcription-polymerase chain reaction (RT-PCR) revealed that IL-6 and its receptors, IL-6 receptor (IL-6R) and gp130, co-existed in the myxoma cells. Myxoma cells were cultured, and an antibody array assay showed that a conditioned medium derived from the cultured myxoma cells contained increased amounts of IL-6. Signal transducer and activator of transcription (STAT) 3 and Akt were constitutively phosphorylated in the myxoma cells. An enzyme-linked immunosorbent assay (ELISA) showed that the myxoma cells spontaneously secreted IL-6 into the culture medium. Real-time PCR revealed that stimulation with IL-6 + soluble IL-6R (sIL6R) significantly increased IL-6 mRNA in the myxoma cells. Pharmacological inhibitors of STAT3 and Akt inhibited the IL-6 + sIL-6R-induced gene expression of IL-6 and the spontaneous secretion of IL-6. In addition, IL-6 + sIL-6R-induced translocation of phosphorylated STAT3 to the nucleus was also blocked by STAT3 inhibitors. This study has demonstrated that IL-6 increases its own production via STAT3 and Akt pathways in cardiac myxoma cells. Autocrine regulation of IL-6 may play an important role in the pathophysiology of patients with cardiac myxoma.
... This activation is followed by recruitment of mononuclear cells, stimulation of endothelial cells, stimulation of smooth muscle cells, inhibition of T cell apoptosis, and inhibition of T-reg differentiation. Anti-inflammatory and protective effects are mediated by gp130 signaling activation followed by epithelial cell proliferation, inhibition of epithelial apoptosis, IL-6-dependent liver, pancreas, or other tissue regeneration, hepatic acute phase reaction inhibition, and defense against bacterial infections (Rose-John, 2012). ...
Nine soluble ligands [interleukin-6 (IL-6), interleukin-11 (IL-11), leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine, interleukin-27 (IL-27), and interleukin-31] share the ubiquitously expressed transmembrane protein-glycoprotein-130 beta-subunit (gp130) and thus form IL-6 family cytokines. Proteins that may be important for cancerogenesis, CT-1, IL-11, IL-27, LIF, OSM, and CNTF, belong to the superfamily of IL-6. Cytokines such as IL-6, IL-11, and IL-27 are better investigated in comparison with other members of the same family of cytokines, eg, CT-1. Gp130 is one of the main receptors through which these cytokines exert their effects. The clinical implication of understanding the pathways of these cytokines in oncology is that targeted therapy to inhibit or potentiate cytokine activity may lead to remission in some cases.
