Affinage

Showing IL6 — HSF is a alias.

IL6

Interleukin-6 · UniProt P05231

Length
212 aa
Mass
23.7 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IL-6 is a pleiotropic secreted cytokine that orchestrates immune cell fate, tissue repair, and metabolic responses by signaling through a two-chain receptor system in which a ligand-binding chain (IL-6R) captures IL-6 and triggers association with the signal-transducing chain gp130, the latter forming high-affinity binding sites and transducing the intracellular signal (PMID:1618596). The active signaling complex assembles into higher-order tetrameric/hexameric stoichiometries, and a ligand-induced transition to an inactive hexamer can act as a switch that limits signaling at supraoptimal cytokine concentrations (PMID:10494829). IL-6 also acts via trans-signaling, in which the IL-6/soluble IL-6R complex agonizes gp130 on cells lacking membrane IL-6R, a mechanism that drives chronic inflammatory disease including bowel inflammation, rheumatoid arthritis, and crescentic nephritis (PMID:15871661, PMID:26041841). Downstream, IL-6 engages a JAK2-STAT3 axis that phosphorylates STAT3 to control target gene transcription — driving RANKL for osteoclastogenesis (PMID:28278513), CSF1R for macrophage survival (PMID:37539077), and immunosuppressive programs (CCR5/arginase-1) in MDSC (PMID:32788238) — and JAK2 also phosphorylates BECN1 at Y333 to activate PI3KC3-dependent autophagy (PMID:34131122). The cytokine is a central determinant of T cell fate, cooperating with TGF-β to induce Th17 differentiation while suppressing Treg differentiation (PMID:20583029), reducing apoptosis of antigen-stimulated CD4 T cells (PMID:15814701), and inducing IL-17 production in NK cells via RORγt (PMID:20083665). Beyond immunity, IL-6 promotes intestinal epithelial proliferation and crypt homeostasis through a Paneth cell pSTAT3-Wnt axis (PMID:28550196), activates AMPK to stimulate fatty acid oxidation and GLUT4-mediated glucose uptake in muscle (PMID:17956334), and sustains autocrine senescence in pituitary tumor cells (PMID:27902467). Signaling is terminated by SOCS3, which binds gp130 and JAK1/JAK2/TYK2 simultaneously (via a GQM motif in the kinase domain) and occludes the substrate groove in an ATP-independent manner (PMID:24418198). IL-6 transcription itself is tightly controlled by transcription factors NF-IL6/C/EBP, NF-κB, and STAT3 together with epigenetic machinery, including Tet2-Hdac2-mediated histone deacetylation for resolution-phase repression (PMID:26287468), Kdm6a-mediated H3K27 demethylation for induction (PMID:28284523), and YY1 phase-separation enhancer complexes (PMID:37094986).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1992 High

    Established the architecture of IL-6 reception by resolving that ligand binding and signal transduction are split between two membrane chains, defining how IL-6 can be sensed and propagated.

    Evidence Receptor binding and signal transduction studies of IL-6R and gp130

    PMID:1618596

    Open questions at the time
    • Stoichiometry of the active complex not resolved here
    • Intracellular effectors of gp130 not yet defined
  2. 1992 High

    Identified NF-IL6/C/EBP as the DNA-binding factor coupling inflammatory stimuli to IL-6 gene induction, linking IL-6 transcription to the acute-phase response.

    Evidence Direct cloning and DNA-binding assays identifying NF-IL6 at IL-6 regulatory regions

    PMID:1380488

    Open questions at the time
    • Combinatorial control with other factors not defined
    • No chromatin-level mechanism established
  3. 1999 Medium

    Proposed that receptor complex stoichiometry (tetramer-to-hexamer transition) functions as a built-in molecular switch limiting signaling at high ligand, addressing how IL-6 responses are self-limited.

    Evidence Structural and biochemical analysis of IL-6/IL-6R/gp130 complex stoichiometry

    PMID:10494829

    Open questions at the time
    • Single-lab structural model not independently replicated at publication
    • Physiological relevance of the switch in vivo unresolved
  4. 2005 High

    Defined IL-6 trans-signaling, showing the soluble IL-6R/IL-6 complex extends responsiveness to gp130-bearing cells lacking IL-6R, explaining IL-6's role in chronic inflammation.

    Evidence In vivo mouse disease models and recombinant protein signaling assays

    PMID:15871661

    Open questions at the time
    • Cellular source of sIL-6R per tissue not fully mapped
    • Relative contribution of classic vs trans-signaling per disease unclear
  5. 2005 High

    Showed IL-6 shapes adaptive immunity by reducing apoptosis of divided antigen-stimulated CD4 T cells, establishing its role in memory/effector T cell accumulation.

    Evidence CFSE/BrdU/annexin V assays in transgenic T cell transfer and IL-6 KO mice

    PMID:15814701

    Open questions at the time
    • Downstream survival effectors not identified
    • Single-lab finding
  6. 2010 High

    Placed IL-6 at the center of the Treg/Th17 decision, demonstrating it cooperates with TGF-β to drive Th17 while blocking Treg differentiation, and extends Th17-like programs to NK cells.

    Evidence T cell differentiation assays and KO mice; RORγt analysis in NK cells in T. gondii infection

    PMID:20083665 PMID:20583029

    Open questions at the time
    • Transcriptional logic of the Treg/Th17 switch not fully detailed
    • NK IL-6R expression heterogeneity not explained
  7. 2014 High

    Resolved the structural basis of IL-6 signal termination, showing SOCS3 simultaneously engages gp130 and specific JAKs to occlude the kinase substrate groove.

    Evidence Biochemical binding, structural studies, and mutagenesis of the JAK GQM motif

    PMID:24418198

    Open questions at the time
    • Kinetics of SOCS3 induction vs signaling not quantified
    • JAK3 exclusion mechanism beyond GQM not addressed
  8. 2015 High

    Connected IL-6 gene control to active epigenetic repression, showing Tet2 (targeted by IκBζ) recruits Hdac2 to deacetylate the Il6 promoter independently of DNA methylation during inflammation resolution.

    Evidence ChIP, Tet2-deficient mice, LPS challenge, histone modification assays

    PMID:26287468

    Open questions at the time
    • Signals triggering resolution-phase Tet2 recruitment not fully defined
    • Generalizability beyond myeloid cells unclear
  9. 2017 High

    Identified the opposing inductive epigenetic arm, with Kdm6a demethylating H3K27me3 at the IL-6 promoter to permit expression during innate responses.

    Evidence ChIP, enzymatic-dead mutants, and primary macrophage knockdown

    PMID:28284523

    Open questions at the time
    • Upstream signals recruiting Kdm6a not defined
    • Interplay with Tet2-Hdac2 repression not mapped
  10. 2017 Medium

    Linked IL-6/JAK2/STAT3 signaling to bone remodeling, showing it raises RANKL to enhance osteocyte-mediated osteoclastogenesis.

    Evidence RT-PCR, Western blot, TRAP staining, co-culture, and JAK2 inhibition (AG490)

    PMID:28278513

    Open questions at the time
    • Direct vs indirect STAT3 control of RANKL promoter not resolved
    • Single cell-line system
  11. 2021 High

    Expanded IL-6's intracellular reach to autophagy, demonstrating JAK2 phosphorylates BECN1 at Y333 to drive PI3KC3 complex formation and chemoresistance.

    Evidence Co-IP, in vitro kinase assay, Y333 mutagenesis, autophagy flux, and cancer models

    PMID:34131122

    Open questions at the time
    • Receptor-proximal coupling to cytosolic JAK2-BECN1 not fully mapped
    • Generalizability beyond colorectal cancer unclear
  12. 2021 Medium

    Showed IL-6 metabolically reprograms muscle, rapidly activating AMPK to drive fatty acid oxidation and GLUT4-dependent glucose uptake.

    Evidence Myotube metabolic assays with AMPK dominant-negative expression

    PMID:17956334

    Open questions at the time
    • Receptor route (classic vs trans) in myotubes not specified
    • Single-lab finding
  13. 2023 High

    Defined the cellular source and induction of IL-6 in injured heart, showing cardiac fibroblasts produce IL-6 via adenosine/A2bR/Gq signaling fed by T cell-derived adenosine.

    Evidence scRNA-seq (mouse and human), RNAscope, CD4-CD73 KO mice, receptor pharmacology

    PMID:36943408

    Open questions at the time
    • Downstream cardiac consequences of fibroblast IL-6 not detailed here
    • Translation to human cardiac outcomes pending
  14. 2023 High

    Revealed enhancer-level control of IL-6 in tumor-associated macrophages, with YY1 liquid-liquid phase separation organizing p300/p65/CEBPB to drive M2-specific enhancer-promoter looping.

    Evidence H3K27ac/YY1 ChIP-seq, CRISPR KO, LLPS assays, chromatin interaction analysis

    PMID:37094986

    Open questions at the time
    • Triggers of YY1 condensate formation not defined
    • Relationship to NF-IL6/STAT3 promoter control unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the receptor-proximal JAK-STAT3 module is integrated with the diverse downstream effectors (autophagy, AMPK metabolism, senescence) and the multilayered transcriptional/epigenetic control of the IL-6 gene into a unified, context-dependent response remains unresolved.
  • No single framework reconciles classic vs trans-signaling outputs across tissues
  • Quantitative integration of activating (Kdm6a, YY1) and repressive (Tet2-Hdac2) IL-6 transcription not established
  • Structural basis of the proposed hexamer off-switch in vivo not confirmed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 2 GO:0060089 molecular transducer activity 2
Localization
GO:0005576 extracellular region 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
BECN1IL6RIL6STJAK2SOCS3STAT3
Complex memberships
IL-6/IL-6R/gp130 signaling complex

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 IL-6 receptor system consists of two membrane proteins: a ligand-binding chain (IL-6R) and a non-ligand-binding signal transducer gp130. Binding of IL-6 to IL-6R triggers the association of IL-6R and gp130, and gp130 transduces the signal. Despite lacking IL-6 binding property, gp130 is involved in the formation of high-affinity IL-6 binding sites. Receptor binding and signal transduction studies International journal of immunopharmacology High 1618596
1992 NF-IL6 (C/EBP homolog) is a DNA-binding protein responsible for IL-1-stimulated IL-6 induction and is identical to IL-6DBP, the DNA-binding protein responsible for IL-6-mediated induction of acute-phase proteins. NF-IL6 binds to regulatory regions of the IL-6 gene and various other inducible genes involved in acute, immune, and inflammatory responses. Direct cloning, DNA binding assay, transcription factor identification Immunological reviews High 1380488
1999 IL-6 type cytokine active signaling complexes with IL-6R and gp130 may exist as tetramers or hexamers; a model is proposed in which ligand-induced transition from an active tetrameric to an inactive hexameric complex serves as a molecular switch that turns off IL-6 signals at supraoptimal cytokine concentrations. Structural and biochemical analysis of receptor complex stoichiometry Biological chemistry Medium 10494829
2005 IL-6 transsignaling: the IL-6/soluble IL-6 receptor (sIL-6R) complex acts as an agonist by binding to gp130 on cells that do not express membrane-bound IL-6R, thereby expanding IL-6 responsiveness. This trans-signaling is a crucial mechanism in chronic inflammatory diseases including inflammatory bowel disease, peritonitis, rheumatoid arthritis, and colon cancer. In vivo mouse models, recombinant protein studies, cell signaling assays Journal of interferon & cytokine research High 15871661
2005 IL-6 reduces the level of apoptosis among antigen-stimulated CD4 T cells (particularly those that have undergone five or more divisions) as shown by reduced annexin V staining, without affecting proliferative rates, thereby playing a central role in determining numbers of memory/effector CD4 T cells after immunization. CFSE dilution, BrdU labeling, annexin V staining in transgenic T cell transfer model, IL-6 KO mice Journal of immunology High 15814701
2002 IL-6 promotes Th2 differentiation through activation of NFAT-mediated transcription leading to IL-4 production by naive CD4+ T cells, while simultaneously inhibiting Th1 differentiation through an IL-4- and NFAT-independent mechanism involving upregulation of SOCS-1 to interfere with IFNγ signaling. T cell differentiation assays, reporter assays, SOCS-1 expression analysis Molecular immunology Medium 12431386
2010 IL-6, together with TGF-β, induces differentiation of Th17 cells from naive T cells, while IL-6 also inhibits TGF-β-induced regulatory T cell (Treg) differentiation, thereby regulating the Treg/Th17 balance. T cell differentiation assays, cytokine stimulation, KO mouse models European journal of immunology High 20583029
2014 SOCS3 is the primary inhibitor of IL-6 signaling. Biochemical and structural studies show SOCS3 binds to gp130 and to JAK1, JAK2 and TYK2 (but not JAK3), with specificity determined by a three-residue 'GQM' motif in the kinase domain of JAK1, JAK2 and TYK2. SOCS3 binds JAK and gp130 simultaneously and inhibits JAK activity in an ATP-independent manner by partially occluding the substrate binding groove with its kinase inhibitory region. Biochemical binding assays, structural studies, mutagenesis of JAK kinase domain Seminars in immunology High 24418198
2015 Tet2 selectively mediates active repression of IL-6 transcription during inflammation resolution in innate myeloid cells. IκBζ mediates specific targeting of Tet2 to the Il6 promoter. Independent of DNA methylation and hydroxymethylation, Tet2 recruits Hdac2 and represses IL-6 transcription via histone deacetylation. Chromatin immunoprecipitation, Tet2-deficient mice, LPS challenge, gene-specific promoter analysis, histone modification assays Nature High 26287468
2010 IL-6 upregulates expression of RORγt (Th17-associated transcription factor) in NK cells and promotes IL-17 production. Only a subset of NK cells expresses both chains of the IL-6R. IL-6-deficient mice challenged with T. gondii had a major defect in NK cell production of IL-17. IL-6 KO mice, T. gondii infection model, flow cytometry, RORγt expression analysis Journal of immunology High 20083665
2021 IL-6 activates autophagy through the IL-6/JAK2/BECN1 pathway. IL-6 triggers the interaction between JAK2 and BECN1, where JAK2 phosphorylates BECN1 at Y333. BECN1 Y333 phosphorylation is crucial for BECN1 activation and IL-6-induced autophagy by regulating PI3KC3 complex formation, and promotes chemotherapy resistance in colorectal cancer. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (Y333), autophagy flux assays, cancer cell lines and in vivo models Nature communications High 34131122
2017 IL-6 enhances osteocyte-mediated osteoclastogenesis by promoting JAK2 phosphorylation and STAT3 activation, which in turn increases RANKL expression at both mRNA and protein levels. Inhibition of JAK2 with AG490 suppressed phospho-JAK2 and RANKL expression and reduced osteoclastic differentiation. RT-PCR, Western blotting, TRAP staining, co-culture assay, JAK2 inhibitor AG490 Cellular physiology and biochemistry Medium 28278513
2012 c-Src stimulates IL-6 expression through STAT3, and IL-6 in turn induces IGFBP5 which activates c-Src, forming an amplification loop in immature osteoblasts. In mature osteoblasts this loop is broken because c-Src is downregulated. IGFBP5 produced by osteoblasts stimulates osteoclastogenesis, acting as an osteoblast-osteoclast coupling factor. In vitro and in vivo osteoblast differentiation assays, STAT3 reporter, siRNA knockdown, mouse models Nature communications High 22252554
2005 In neural stem cell differentiation, IL-6 family cytokines and BMPs act synergistically to induce astrocyte differentiation. This cooperation involves formation of a complex between STAT3 (downstream of IL-6 family cytokines) and Smad1 (downstream of BMPs), bridged by the transcriptional coactivator p300. A STAT3 binding element in the GFAP promoter is regulated by DNA methylation during brain development. Transcription factor complex analysis, promoter luciferase assays, DNA methylation analysis, neuroepithelial cell culture Clinical reviews in allergy & immunology Medium 16129909
2017 Demethylase Kdm6a promotes IL-6 expression in macrophages through demethylating H3K27me3 at the IL-6 promoter in a demethylase enzymatic activity-dependent manner during innate immune responses. Chromatin immunoprecipitation, enzymatic activity-deficient mutants, primary macrophage knockdown, H3K27me3 histone modification assays Journal of autoimmunity High 28284523
2014 IL-6 stimulates intestinal epithelial proliferation and wound repair. Inhibition of IL-6 resulted in impaired wound healing due to decreased epithelial proliferation in two murine models of bowel injury (biopsy wound and bacterial-triggered colitis). IL-6 is induced after injury by multiple cell types including intraepithelial lymphocytes. Two murine bowel injury models, IL-6 inhibition, epithelial proliferation assays, human tissue analysis PloS one Medium 25478789
2017 Autocrine IL-6 signaling in intestinal crypt epithelium regulates crypt homeostasis through Paneth cells via pSTAT3 activation and the Wnt signaling pathway. IL-6 receptor is restricted to the basal membrane of Paneth cells. IL-6-induced crypt organoid proliferation was abrogated by the Wnt inhibitor IWP2. Mouse intestinal crypt organoids, in vivo mouse model, IL-6R blocking antibody, Wnt inhibitor IWP2, immunolabeling, IL-6 neutralizing antibody Journal of immunology High 28550196
2023 Post-myocardial infarction IL-6 is preferentially produced by cardiac fibroblasts (CFs). Adenosine stimulates fibroblast IL-6 formation via the adenosine receptor A2bR in a Gq-dependent manner. T cell-derived adenosine (from CD73 on T cells) modulates IL-6 formation in CFs, representing purinergic metabolic cooperation between CFs and T cells. Single-cell RNA-seq (mouse and human hearts), quantitative PCR, RNAscope, protein-level cell-type analysis, genetic mouse models (CD4-CD73-/-), in vitro receptor pharmacology The Journal of clinical investigation High 36943408
2013 IL-6 functions downstream of IL-17A to exacerbate neutrophil microabscess development in psoriasiform skin lesions. IL-17A expression results in upregulated granulopoiesis and migration of IL-6R-expressing neutrophils into the skin. Neutralization of IL-6 signaling efficiently reduced epidermal neutrophil abscess formation and epidermal thickening. Transgenic IL-17A skin mouse model, IL-6 neutralization, histopathology, granulopoiesis analysis The Journal of investigative dermatology Medium 24067382
2023 IL-6 signaling in Tet2-deficient macrophages induces Csf1r expression through enhanced STAT3 binding to the CSF1R promoter, increasing macrophage survival and contributing to accelerated atherosclerosis in clonal hematopoiesis. IL-6 receptor antibody treatment reverses Tet2-deficient clonal hematopoiesis-promoted atherosclerosis. ChIP for STAT3 at Csf1r promoter, mouse and human Tet2-deficient macrophages, IL-6R antibody treatment, CSF1R inhibitor PLX3397, atherosclerosis mouse model Nature cardiovascular research High 37539077
2023 Phase separation of the YY1 complex in M2 macrophages upregulates IL-6 by promoting IL-6 enhancer-promoter interactions via long-range chromatin interaction. An M2-specific IL-6 enhancer was identified; YY1 formed a liquid-liquid phase separation in which p300, p65, and CEBPB acted as transcriptional cofactors to drive IL-6 expression. H3K27ac-ChIP-seq, YY1 ChIP-seq, CRISPR-Cas9 knockout, RNA-seq, liquid-liquid phase separation assays, chromatin interaction analysis Journal for immunotherapy of cancer High 37094986
2021 IL-6 signaling in macrophages is critical for immunotherapy-driven tumor regression. IL-6 receptor signaling in macrophages is required for effective M1-type macrophage function; IL-6 signaling blockade decreased SOCS3 expression in macrophages and increased expression of the phagocytic checkpoint molecule SIRPα. Macrophage-specific IL-6R deletion (Il6rafl/fl×LysMcre+) impaired therapy efficacy without affecting vaccine-induced CD8+ T cell responses. Macrophage-specific conditional IL-6R knockout mice, therapeutic vaccination tumor model, flow cytometry, SOCS3 and SIRPα expression analysis Journal for immunotherapy of cancer High 33879600
2021 IL-6 upregulates CCR5 expression and arginase 1 in MDSC through a STAT3-dependent mechanism, enhancing their immunosuppressive capacity. MDSC differentiated in the presence of IL-6 strongly inhibited CD8+ T cell functions compared with MDSC differentiated without IL-6. Correlation between IL-6 levels, phosphorylated STAT3, and CCR5 expression was demonstrated in tumor-infiltrating MDSC in a transgenic melanoma model. In vitro MDSC differentiation, STAT3 phosphorylation analysis, mRNA/protein expression, RET transgenic melanoma mouse model, CD8+ T cell suppression assay Journal for immunotherapy of cancer Medium 32788238
2016 IL-6 treatment of myotubes increases fatty acid oxidation, basal and insulin-stimulated glucose uptake, and translocation of GLUT4 to the plasma membrane. IL-6 rapidly and markedly increases AMPK activity, and the metabolic effects of IL-6 were abrogated in AMPK dominant-negative infected cells. Myotube cell culture, fatty acid oxidation assay, glucose uptake assay, GLUT4 translocation assay, AMPK dominant-negative expression Biochemical Society transactions Medium 17956334
2014 IL-6 inhibits allograft acceptance by promoting T cell alloimmune responses and impairing the ability of regulatory T cells to suppress effector T cell alloimmunity. Absence of both IL-6 and TNF-α in the graft recipient synergized with co-stimulatory blockade to induce tolerance. Murine skin allograft model, IL-6/TNF-α double KO, co-stimulatory blockade, in vitro and in vivo T cell assays Journal of the American Society of Nephrology Medium 19357252
2011 CK2 (protein kinase CK2) regulates IL-6 expression in inflammatory breast cancer. siRNA knockdown of CK2 and the selective CK2 inhibitor CX-4945 suppressed IL-6 expression and secretion in vitro and in vivo. CK2 inhibition also reduced plasma IL-6 levels in a clinical trial patient. siRNA knockdown, small molecule inhibitor (CX-4945), ELISA, in vitro and in vivo cancer models, clinical sample analysis Biochemical and biophysical research communications Medium 22027148
2014 The BET bromodomain protein inhibitor I-BET151 selectively inhibits IL-6 production (but not TNFα, IL-1β, or IL-10) in LPS-stimulated macrophages by preventing the binding of CBP to the IL-6 promoter, without affecting NF-κB acetylation, phosphorylation, nuclear translocation, or DNA binding. Chromatin immunoprecipitation (CBP binding at IL-6 promoter), cytokine ELISA, NF-κB activity assays, LPS-stimulated RAW264.7 cells Biochimica et biophysica acta Medium 24859008
2015 IL-6 trans-signaling via soluble IL-6R drives crescentic nephritis. Specific inhibition of IL-6 trans-signaling using recombinant sgp130Fc resulted in milder nephritis, while specific activation using a recombinant IL-6-sIL-6R fusion molecule (Hyper-IL-6) significantly aggravated disease and increased systolic BP. Simultaneous inhibition of both IL-6 signaling pathways using anti-IL-6 antibody alone had no significant impact. Nephrotoxic serum-induced nephritis mouse model, recombinant sgp130Fc (trans-signaling specific inhibitor), Hyper-IL-6 fusion protein, pSTAT3/SOCS3 analysis, Th17 cytokine measurement Journal of the American Society of Nephrology High 26041841
2017 Autocrine IL-6 maintains cellular senescence in pituitary somatotroph tumor cells. Endogenous IL-6 inhibition via shRNA in MtT/S clones decreased SA-β-gal activity and p16INK4a but increased pRb and proliferation/invasion. IL-6-silenced clones became tumorigenic in nude mice, while wild-type MtT/S cells did not, demonstrating that escape from IL-6-driven senescence enables malignant transformation. shRNA stable knockdown, SA-β-gal staining, p16INK4a/pRb Western blot, nude mouse xenograft, human pituitary tumor samples Oncotarget Medium 27902467
2020 In human astrocytes, β-catenin in complex with TCF/LEF inhibits IL-6 transcription, while TCF/LEF independent of β-catenin induces IL-6 transcription through interaction with ATF-2/SMADs. β-catenin independent of TCFs/LEF positively regulates C/EBP and NF-κB to activate IL-6 expression. Two TCF/LEF binding sites in the IL-6 promoter were identified (at -91 nt and -948 nt from TSS), both required for TCF/LEF induction of IL-6. siRNA knockdown, cDNA overexpression, IL-6 promoter luciferase reporter, site-directed mutagenesis of promoter sites, chromatin immunoprecipitation, pharmacological agents Cell communication and signaling Medium 32546183
2004 IL-6 strongly increases CD44 gene expression in multiple myeloma cells, modulates CD44 RNA alternative splicing inducing overexpression of all CD44 variant exons, and induces a functional polarized membrane distribution of CD44 cell surface molecules. RT-PCR, Western blot, flow cytometry, cell surface distribution analysis in myeloma cell lines Leukemia Medium 15014527

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 IL-6 in inflammation, immunity, and disease. Cold Spring Harbor perspectives in biology 3657 25190079
2015 IL-6 as a keystone cytokine in health and disease. Nature immunology 1901 25898198
2010 IL-6: regulator of Treg/Th17 balance. European journal of immunology 1292 20583029
2016 IL-6 pathway in the liver: From physiopathology to therapy. Journal of hepatology 714 26867490
2002 The two faces of IL-6 on Th1/Th2 differentiation. Molecular immunology 696 12431386
2015 Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature 680 26287468
2010 IL-6: from its discovery to clinical applications. International immunology 617 20410258
2018 Rethinking IL-6 and CRP: Why they are more than inflammatory biomarkers, and why it matters. Brain, behavior, and immunity 598 29499302
2014 The two faces of IL-6 in the tumor microenvironment. Seminars in immunology 566 24602448
2016 Immunotherapeutic implications of IL-6 blockade for cytokine storm. Immunotherapy 498 27381687
2020 Translating IL-6 biology into effective treatments. Nature reviews. Rheumatology 495 32327746
1992 IL-6 and NF-IL6 in acute-phase response and viral infection. Immunological reviews 472 1380488
2003 Searching for the exercise factor: is IL-6 a candidate? Journal of muscle research and cell motility 396 14609022
2002 The paradigm of IL-6: from basic science to medicine. Arthritis research 368 12110143
2020 A panoramic review of IL-6: Structure, pathophysiological roles and inhibitors. Bioorganic & medicinal chemistry 341 31992476
2015 Versatile functions for IL-6 in metabolism and cancer. Trends in immunology 301 25616716
2018 Interleukin (IL-6) Immunotherapy. Cold Spring Harbor perspectives in biology 300 28778870
2013 The role of intratumoral and systemic IL-6 in breast cancer. Breast cancer research and treatment 289 23532539
2015 The varying faces of IL-6: From cardiac protection to cardiac failure. Cytokine 268 25649043
2014 IL-6 biology: implications for clinical targeting in rheumatic disease. Nature reviews. Rheumatology 242 25136784
2018 IL-6 and ovarian cancer: inflammatory cytokines in promotion of metastasis. Cancer management and research 230 30584363
2014 IL-6 stimulates intestinal epithelial proliferation and repair after injury. PloS one 219 25478789
2005 IL-6 transsignaling: the in vivo consequences. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 208 15871661
2021 IL-6 regulates autophagy and chemotherapy resistance by promoting BECN1 phosphorylation. Nature communications 205 34131122
2017 IL-6 Enhances Osteocyte-Mediated Osteoclastogenesis by Promoting JAK2 and RANKL Activity In Vitro. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 202 28278513
2016 Skeletal muscle wasting and renewal: a pivotal role of myokine IL-6. SpringerPlus 191 27330885
2010 IL-6 promotes NK cell production of IL-17 during toxoplasmosis. Journal of immunology (Baltimore, Md. : 1950) 176 20083665
2014 Inhibition of IL-6 family cytokines by SOCS3. Seminars in immunology 170 24418198
2016 Regulation of IL-6 in Immunity and Diseases. Advances in experimental medicine and biology 168 27734409
1991 Regulation of IL-6 expression by oncostatin M. Journal of immunology (Baltimore, Md. : 1950) 154 1918953
2012 IL-6, IL-17 and STAT3: a holy trinity in auto-immunity? Frontiers in bioscience (Landmark edition) 142 22652781
2021 Microenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy. Nature communications 128 34711820
2007 IL-6 signalling in exercise and disease. Biochemical Society transactions 127 17956334
2023 The exercise IL-6 enigma in cancer. Trends in endocrinology and metabolism: TEM 114 37633799
2023 YY1 complex in M2 macrophage promotes prostate cancer progression by upregulating IL-6. Journal for immunotherapy of cancer 111 37094986
2014 Gene of the month: Interleukin 6 (IL-6). Journal of clinical pathology 111 25031389
2017 Nutritional interventions and the IL-6 response to exercise. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 109 28507168
2013 Brain IL-6 and autism. Neuroscience 109 23994594
2020 IL-6 regulates CCR5 expression and immunosuppressive capacity of MDSC in murine melanoma. Journal for immunotherapy of cancer 108 32788238
2005 IL-6 increases primed cell expansion and survival. Journal of immunology (Baltimore, Md. : 1950) 106 15814701
1999 IL-6 type cytokine receptor complexes: hexamer, tetramer or both? Biological chemistry 104 10494829
2022 IL-6: The Link Between Inflammation, Immunity and Breast Cancer. Frontiers in oncology 102 35924148
2012 c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling. Nature communications 100 22252554
2017 IL-6 signaling in diabetic nephropathy: From pathophysiology to therapeutic perspectives. Cytokine & growth factor reviews 98 28363692
2009 Clinical value of blocking IL-6 receptor. Current opinion in rheumatology 97 19365268
2018 IL-6: a cytokine at the crossroads of autoimmunity. Current opinion in immunology 96 30248523
2013 IL-6 regulates neutrophil microabscess formation in IL-17A-driven psoriasiform lesions. The Journal of investigative dermatology 96 24067382
2017 IL-6 Signaling Regulates Small Intestinal Crypt Homeostasis. Journal of immunology (Baltimore, Md. : 1950) 92 28550196
2005 Role of IL-6 in the neural stem cell differentiation. Clinical reviews in allergy & immunology 91 16129909
2021 Role of IL-6 in dendritic cell functions. Journal of leukocyte biology 85 34405445
2014 The IL-6 feed-forward loop: a driver of tumorigenesis. Seminars in immunology 85 24613573
2019 IL-6 Activities in the Tumour Microenvironment. Part 1. Open access Macedonian journal of medical sciences 84 31592285
2009 IL-6 and TNF-alpha synergistically inhibit allograft acceptance. Journal of the American Society of Nephrology : JASN 82 19357252
2018 IL-6 receptor blockade ameliorates diabetic nephropathy via inhibiting inflammasome in mice. Metabolism: clinical and experimental 80 29336982
2010 Involvement of IL-17F via the induction of IL-6 in psoriasis. Archives of dermatological research 75 20148256
2017 Demethylase Kdm6a epigenetically promotes IL-6 and IFN-β production in macrophages. Journal of autoimmunity 73 28284523
2018 IL-6 and CXCL8 mediate osteosarcoma-lung interactions critical to metastasis. JCI insight 71 30135299
2010 Palmitate and insulin synergistically induce IL-6 expression in human monocytes. Cardiovascular diabetology 70 21054880
2024 IL-6 and Cardiovascular Risk: A Narrative Review. Current atherosclerosis reports 68 39589436
2016 Harpagoside suppresses IL-6 expression in primary human osteoarthritis chondrocytes. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 67 27082319
1992 IL-6 receptor and mechanism of signal transduction. International journal of immunopharmacology 65 1618596
2014 IL-6 regulates adipose deposition and homeostasis in lymphedema. American journal of physiology. Heart and circulatory physiology 63 24633552
2023 Blockade of IL-6 signaling alleviates atherosclerosis in Tet2-deficient clonal hematopoiesis. Nature cardiovascular research 61 37539077
2022 Immunotherapy of COVID-19: Inside and Beyond IL-6 Signalling. Frontiers in immunology 61 35340805
2011 Protein kinase CK2 modulates IL-6 expression in inflammatory breast cancer. Biochemical and biophysical research communications 60 22027148
2016 IL-6 roles - Molecular pathway and clinical implication in pancreatic cancer - A systemic review. Immunology letters 59 27876525
2021 IL-6 Directed Therapy in Transplantation. Current transplantation reports 57 34099967
2014 Upregulation of TLRs and IL-6 as a marker in human colorectal cancer. International journal of molecular sciences 57 25547486
2015 IL-6 and Akt are involved in muscular pathogenesis in myasthenia gravis. Acta neuropathologica communications 55 25627031
2011 The value of blocking IL-6 outside of rheumatoid arthritis: current perspective. Current opinion in rheumatology 55 21427577
2005 IL-6: from laboratory to bedside. Clinical reviews in allergy & immunology 55 16129902
2023 IL-6 in the infarcted heart is preferentially formed by fibroblasts and modulated by purinergic signaling. The Journal of clinical investigation 54 36943408
2017 A Role for Soluble IL-6 Receptor in Osteoarthritis. Journal of functional morphology and kinesiology 53 29276788
2007 Essential role of IL-6 signaling pathway in keloid pathogenesis. Journal of Nippon Medical School = Nippon Ika Daigaku zasshi 53 17384473
2016 Revisiting IL-6 antagonism in multiple myeloma. Critical reviews in oncology/hematology 48 27497026
2022 IL-6 and its role in IgA nephropathy development. Cytokine & growth factor reviews 47 35527168
2015 IL-6 Trans-Signaling Drives Murine Crescentic GN. Journal of the American Society of Nephrology : JASN 47 26041841
2003 IL-6 and Crohn's disease. Current drug targets. Inflammation and allergy 47 14561164
2018 IL-6 in Osteoarthritis: Effects of Pine Stilbenoids. Molecules (Basel, Switzerland) 46 30597965
2008 The blockade of IL-6 signaling in rational drug design. Current pharmaceutical design 45 18473869
2021 Therapeutic targeting of IL-6 trans-signaling. Cytokine 42 34022535
2021 IL-6 signaling in macrophages is required for immunotherapy-driven regression of tumors. Journal for immunotherapy of cancer 41 33879600
2021 Inborn errors of IL-6 family cytokine responses. Current opinion in immunology 41 34044328
2015 Relationship among IL-6, LDL cholesterol and lipid peroxidation. Cellular & molecular biology letters 41 26204410
2019 Apigenin Inhibits IL-6 Transcription and Suppresses Esophageal Carcinogenesis. Frontiers in pharmacology 35 31572184
2018 AA amyloidosis - Benefits and prospects of IL-6 inhibitors. Modern rheumatology 35 30132351
2018 Blockade of IL-6 signaling in neuromyelitis optica. Neurochemistry international 35 30342072
2014 Circulating galanin and IL-6 concentrations in gestational diabetes mellitus. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 35 24397394
2014 I-BET151 selectively regulates IL-6 production. Biochimica et biophysica acta 35 24859008
2020 β-Catenin and TCFs/LEF signaling discordantly regulate IL-6 expression in astrocytes. Cell communication and signaling : CCS 32 32546183
2004 IL-6 regulates CD44 cell surface expression on human myeloma cells. Leukemia 32 15014527
2024 IL-6 and diabetic kidney disease. Frontiers in immunology 31 39749325
2023 Inhibition of IL-6 methylation by Saikosaponin C regulates neuroinflammation to alleviate depression. International immunopharmacology 31 36965369
2016 IL-6 trans-signaling is another pathway to upregulate Osteopontin. Cytokine 31 27863335
2012 Immunotherapeutic implication of IL-6 blockade. Immunotherapy 31 22150003
2019 Inhibition of TRPA1 and IL-6 signal alleviates neuropathic pain following chemotherapeutic bortezomib. Physiological research 30 31424261
2022 Targeting Systemic Sclerosis from Pathogenic Mechanisms to Clinical Manifestations: Why IL-6? Biomedicines 29 35203527
2017 Autocrine IL-6 mediates pituitary tumor senescence. Oncotarget 29 27902467
2004 CYP2C and IL-6 expression in breast cancer. Breast (Edinburgh, Scotland) 29 14759713
2017 Programmed cell senescence: role of IL-6 in the pituitary. Journal of molecular endocrinology 28 28381401

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