Affinage

IL6

Interleukin-6 · UniProt P05231

Round 2 corrected
Length
212 aa
Mass
23.7 kDa
Annotated
2026-04-28
130 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IL-6 is a pleiotropic four-helix-bundle cytokine that orchestrates acute-phase responses, immune cell differentiation, metabolic regulation, and tissue remodeling by engaging classical signaling through membrane-bound IL-6Rα/gp130 or trans-signaling through soluble IL-6Rα/gp130, both converging on JAK1/JAK2/TYK2-mediated activation of STAT3, SHP-2/Ras/MAPK, and AMPK pathways (PMID:2788034, PMID:8272873, PMID:21296109, PMID:17956334). Classical signaling drives regenerative and anti-inflammatory programs—including hepatic acute-phase protein and hepcidin induction via STAT3 promoter binding, dendritic cell maturation control, and GLP-1 secretion from intestinal L cells—while trans-signaling preferentially mediates pro-inflammatory activities such as STAT3/SOCS3-dependent progression of Kras-driven pancreatic neoplasia and paracrine promotion of cancer cell invasiveness as part of the senescence-associated secretory phenotype (PMID:2444978, PMID:16835372, PMID:22037645, PMID:21481788, PMID:19597488). IL-6 transcription is tightly regulated by epigenetic mechanisms including Tet2/Hdac2-mediated histone deacetylation at the IL-6 promoter, Kdm6a-catalyzed H3K27me3 demethylation, DNA methylation, and YY1/p300/p65/CEBPB phase-separation complexes that mediate enhancer–promoter looping (PMID:26287468, PMID:28284523, PMID:10329438, PMID:37094986). Downstream, JAK2 directly phosphorylates BECN1 at Y333 to activate PI3KC3 complex-dependent autophagy, while SOCS3 terminates signaling by simultaneously engaging gp130 and JAK kinases to occlude the substrate-binding groove (PMID:34131122, PMID:24418198).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1986 High

    Molecular cloning of IL-6 (BSF-2) established it as a novel interleukin capable of driving B cell terminal differentiation into immunoglobulin-secreting cells, resolving the identity of a long-sought B cell stimulatory factor.

    Evidence cDNA cloning and functional expression in B cells

    PMID:3491322

    Open questions at the time
    • No receptor identified
    • No signaling pathway known
    • Range of target cell types unknown
  2. 1987 High

    Demonstration that IL-6 is the monocyte-derived hepatocyte-stimulating factor driving the acute-phase protein response revealed the liver as a major physiologic target, expanding IL-6 function beyond B cell biology.

    Evidence Neutralizing antibody blockade and recombinant IL-6 treatment of HepG2 cells and primary hepatocytes

    PMID:2444978

    Open questions at the time
    • Mechanism of hepatocyte signaling unknown
    • Receptor complex not yet defined
  3. 1989 High

    Discovery that IL-6Rα must recruit gp130 for signal transduction, and that a soluble IL-6Rα ectodomain can mediate this association extracellularly, established the two-receptor model and the concept of trans-signaling.

    Evidence Co-immunoprecipitation, binding assays, and transfection of transmembrane-deletion mutants in murine cells

    PMID:2788034

    Open questions at the time
    • gp130 not yet cloned
    • Intracellular signaling cascade unknown
    • Physiologic relevance of trans-signaling in vivo unproven
  4. 1990 High

    Molecular cloning of gp130 and reconstitution of high-affinity IL-6 binding sites by co-transfection with IL-6Rα provided the structural basis for the signaling receptor complex and confirmed gp130 as the obligate signal transducer.

    Evidence cDNA cloning, co-transfection binding assays, and growth signal transduction assays in IL-3-dependent cells

    PMID:2261637

    Open questions at the time
    • Kinases coupled to gp130 unknown
    • Downstream transcription factors not identified
  5. 1994 High

    Identification that gp130 constitutively associates with JAK1, JAK2, and TYK2, which are activated upon ligand-induced receptor dimerization, resolved the proximal kinase machinery of IL-6 signaling.

    Evidence Co-immunoprecipitation and kinase activation assays

    PMID:8272873

    Open questions at the time
    • STAT activation downstream of JAKs not yet shown for IL-6 specifically
    • Negative regulators unknown
  6. 1996 High

    Two advances defined downstream effector outputs and trans-signaling physiology: IL-6 was shown to induce VEGF expression via promoter and 5′-UTR elements (linking IL-6 to angiogenesis), and transgenic mouse studies demonstrated that the IL-6/sIL-6R complex dramatically extends IL-6 half-life and drives extramedullary hematopoiesis not achievable by IL-6 alone.

    Evidence Northern blot/reporter assays for VEGF induction; transgenic mouse models with human IL-6 and sIL-6R

    PMID:8557680 PMID:9052874

    Open questions at the time
    • STAT3 not yet directly linked to specific IL-6 gene targets
    • Mechanism of sIL-6R shedding unknown
  7. 1999 Medium

    Demonstration that IL-6 gene silencing in breast carcinoma cells is reversed by demethylation agents established DNA methylation as an epigenetic mechanism controlling IL-6 transcription.

    Evidence 5-aza-2′-deoxycytidine treatment with Northern blot and methylation analysis in MCF-7 cells

    PMID:10329438

    Open questions at the time
    • Specific CpG sites not mapped
    • Methyltransferases responsible not identified
    • Generalizability to non-cancer cells uncertain
  8. 2000 High

    Direct arterio-venous measurements across exercising human muscle proved that contracting skeletal muscle is a major source of circulating IL-6, establishing IL-6 as an exercise-released myokine.

    Evidence Arterial-femoral venous difference with Doppler blood flow and ELISA in exercising humans

    PMID:11080265

    Open questions at the time
    • Intracellular signaling triggering muscle IL-6 release unknown
    • Metabolic targets of exercise-derived IL-6 not fully defined
  9. 2003 High

    Controlled human infusion studies showed IL-6 at exercise-relevant concentrations induces anti-inflammatory mediators (IL-1ra, IL-10, cortisol) without TNF-α, while parallel in vitro work demonstrated IL-6 causes insulin resistance in adipocytes through transcriptional suppression of IRS-1 and GLUT-4, revealing context-dependent metabolic and immune effects.

    Evidence Randomized human IL-6 infusion with cytokine ELISA; recombinant IL-6 treatment of 3T3-L1 adipocytes with Western blot and glucose transport assays

    PMID:12857678 PMID:12952969

    Open questions at the time
    • Signaling pathway mediating adipocyte insulin resistance not fully delineated
    • In vivo adipose tissue effects not confirmed
  10. 2004 High

    Genetic dissection using IL-6−/− and gp130 STAT3-signaling-deficient knockin mice demonstrated that IL-6 regulates dendritic cell maturation in vivo through gp130-mediated STAT3 activation, placing STAT3 as a critical node for IL-6's immunomodulatory functions.

    Evidence IL-6 knockout and gp130FxxQ/FxxQ knockin mice with flow cytometry and STAT3 phosphorylation analysis

    PMID:15356132

    Open questions at the time
    • Target genes downstream of STAT3 in DCs not cataloged
    • Contribution of trans- vs. classical signaling in DC regulation not resolved
  11. 2006 High

    ChIP and promoter-reporter studies showed IL-6 directly activates hepcidin transcription through STAT3 binding to the hepcidin promoter, establishing the molecular mechanism by which IL-6 drives hypoferremia of inflammation.

    Evidence STAT3 knockout/siRNA, ChIP at hepcidin promoter, reporter assays

    PMID:16835372

    Open questions at the time
    • Relative contribution of IL-6 vs. BMP pathway to hepcidin not quantified
    • Role of trans-signaling at the hepcidin locus not tested
  12. 2009 High

    Two studies converged to place IL-6 at the center of oncogenic and senescence-associated feedback circuits: persistent DNA damage signaling (ATM/NBS1/CHK2-dependent) drives IL-6 secretion in the SASP to promote paracrine cancer invasiveness, while an NF-κB→Lin28→let-7 axis derepresses IL-6 translation, enabling IL-6/STAT3/NF-κB positive feedback that maintains Src-initiated transformation.

    Evidence shRNA knockdown of DDR proteins with invasion assays; miRNA inhibitors, reporter assays, and mammosphere formation

    PMID:19597488 PMID:19878981

    Open questions at the time
    • Relative contribution of IL-6 vs. other SASP cytokines to invasiveness not isolated
    • In vivo validation of NF-κB/Lin28/let-7/IL-6 loop limited
  13. 2011 High

    Genetic epistasis in Kras-driven pancreatic cancer models demonstrated that myeloid-derived IL-6 activates STAT3/SOCS3 in ductal cells via trans-signaling and is required for PanIN progression to adenocarcinoma, providing the first in vivo genetic evidence that trans-signaling drives a specific cancer type.

    Evidence KrasG12D mice crossed with IL-6 trans-signaling–deficient and Socs3-knockout models; STAT3 phosphorylation immunohistochemistry

    PMID:21481788

    Open questions at the time
    • Specific IL-6 target genes in ductal transformation not identified
    • Therapeutic targeting of trans-signaling not tested
  14. 2011 High

    IL-6 was shown to stimulate GLP-1 production from intestinal L cells and pancreatic α cells by upregulating proglucagon and prohormone convertase 1/3, linking IL-6 to incretin-mediated glucose homeostasis.

    Evidence IL-6 administration in mice and humans, GLP-1 ELISA, gene/protein expression in L cells and α cells

    PMID:22037645

    Open questions at the time
    • Signaling intermediaries (STAT3 vs. MAPK) in L/α cells not resolved
    • Chronic vs. acute IL-6 effects on incretin axis not distinguished
  15. 2015 High

    Tet2 was identified as a selective transcriptional repressor of IL-6 that recruits Hdac2 to the IL-6 promoter independently of its DNA demethylase activity; IκBζ directs Tet2 to the locus, and Tet2 loss elevates IL-6 and worsens endotoxin shock and colitis.

    Evidence Tet2-knockout mice, Tet2–Hdac2 co-IP, ChIP at IL-6 promoter, HDAC inhibitor experiments, luciferase reporters

    PMID:26287468

    Open questions at the time
    • Whether Tet2 represses IL-6 in non-myeloid cells unknown
    • Crystal structure of Tet2–Hdac2 complex lacking
  16. 2017 High

    Multiple layers of IL-6 regulation and effector function were refined: Kdm6a promotes IL-6 transcription by demethylating H3K27me3 at the promoter; IL-6 activates JAK2/STAT3 to upregulate RANKL in osteocytes, driving osteoclastogenesis; and SOCS3 terminates IL-6 signaling by simultaneously binding gp130 and JAK kinases to occlude the substrate-binding groove.

    Evidence ChIP-seq and enzymatic mutants in macrophages; JAK2 inhibitor in osteocyte-like cells; structural/biochemical domain analysis of SOCS3

    PMID:24418198 PMID:28278513 PMID:28284523

    Open questions at the time
    • Relative contribution of Kdm6a vs. Tet2 in setting IL-6 transcription threshold not tested
    • Structural basis of SOCS3 specificity for gp130 over other cytokine receptors not fully resolved
  17. 2021 High

    Identification of BECN1 Y333 as a direct JAK2 phosphorylation substrate upon IL-6 stimulation revealed a non-canonical branch of IL-6 signaling that activates autophagy via PI3KC3 complex assembly, contributing to chemotherapy resistance.

    Evidence In vitro kinase assay, site-directed mutagenesis of BECN1 Y333, PI3KC3 complex immunoprecipitation, autophagy flux assays in colorectal cancer cells

    PMID:34131122

    Open questions at the time
    • Whether BECN1 Y333 phosphorylation occurs downstream of trans- vs. classical signaling not tested
    • In vivo validation in animal tumor models limited
  18. 2023 High

    Two studies addressed IL-6 transcriptional control and therapeutic targeting: YY1 forms liquid-liquid phase separation condensates with p300/p65/CEBPB to drive enhancer–promoter looping at the IL-6 locus in M2 macrophages, and IL-6R antibody blockade reverses Tet2-deficiency-driven atherosclerosis by reducing STAT3 binding at the Csf1r promoter.

    Evidence CRISPR-KO, ChIP-seq, LLPS assays, and chromatin conformation studies; IL-6R antibody treatment in Tet2 CH mice with STAT3 ChIP at Csf1r

    PMID:37094986 PMID:37539077

    Open questions at the time
    • Whether YY1 LLPS mechanism generalizes to other IL-6-producing cell types unknown
    • Long-term safety and efficacy of IL-6R blockade in clonal hematopoiesis patients not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how classical and trans-signaling are quantitatively balanced in specific tissues, the full repertoire of direct STAT3 target genes in different IL-6-responsive cell types, and whether the JAK2/BECN1 autophagy axis operates in physiologic (non-cancer) contexts.
  • Tissue-specific quantitative balance of classical vs. trans-signaling
  • Complete catalog of direct IL-6/STAT3 target genes across cell types
  • Physiologic relevance of JAK2-BECN1 autophagy outside cancer

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6 GO:0048018 receptor ligand activity 4
Localization
GO:0005576 extracellular region 6
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-168256 Immune System 6 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1430728 Metabolism 3 R-HSA-1643685 Disease 3 R-HSA-9612973 Autophagy 1
Partners
BECN1IL6RIL6STJAK1JAK2SOCS3STAT3TYK2
Complex memberships
IL-6/IL-6Rα/gp130 hexameric signaling complexIL-6/sIL-6Rα trans-signaling complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1986 IL-6 (originally identified as BSF-2) was cloned from human cDNA, revealing it is a novel interleukin of 184 amino acids that induces final maturation of B cells into immunoglobulin-secreting cells. cDNA cloning, structural analysis, and functional expression in B cells Nature High 3491322
1987 IL-6 (IFN-beta 2/BSF-2) was shown to be the monocyte-derived hepatocyte-stimulating factor that drives the major acute-phase protein response in liver cells, establishing the liver as a primary physiologic target of IL-6. Neutralizing antibody experiments, recombinant protein treatment of HepG2 cells and primary rat hepatocytes, Northern analysis Proceedings of the National Academy of Sciences of the United States of America High 2444978
1989 IL-6 signaling requires its receptor (IL-6-R, 80 kDa) to trigger association with a second non-ligand-binding membrane glycoprotein, gp130; this association is temperature-dependent (occurs at 37°C but not 0°C) and a soluble IL-6-R lacking transmembrane/intracytoplasmic domains can associate with gp130 extracellularly and mediate IL-6 signaling (trans-signaling). Co-immunoprecipitation, binding assays, transfection of mutant receptors in murine cells Cell High 2788034
1989 IL-1β stimulation of human endothelial cells markedly increases (10-15-fold) IL-6 production, confirmed by anti-IL-6 antibody inhibition of hybridoma growth factor activity and Northern blot analysis of IL-6 mRNA; IL-6 itself did not alter endothelial cell function (proliferation, procoagulant activity, prostacyclin, or PMN adhesion). Bioassay (HGF on 7TD1 cells), neutralizing antibodies, Northern blot, functional assays Journal of immunology High 2783442
1990 IL-6 is produced by osteoblasts in response to local bone-resorbing agents (IL-1α, IL-1β, TNF-α, LPS) and itself induces bone resorption by increasing osteoclast numbers, and acts cooperatively with IL-1α at suboptimal concentrations. RT-PCR/Northern blot for IL-6 mRNA, 45Ca release assay, osteoclast counting in histological sections Journal of immunology High 2121824
1990 gp130 was molecularly cloned (918 amino acids, single transmembrane domain, extracellular fibronectin type III modules). gp130 alone does not bind IL-6 but co-transfection with IL-6-R cDNA generates high-affinity IL-6 binding sites. gp130 associates with the IL-6/soluble IL-6-R complex extracellularly and transduces the growth signal. cDNA cloning, binding assays, co-transfection experiments, growth signal transduction assay in IL-3-dependent cell line Cell High 2261637
1991 Oncostatin M (OncM) stimulates IL-6 production in human endothelial cells in a time- and dose-dependent manner (>10-fold at 6 h), associated with a 7-fold increase in IL-6 mRNA; IL-1α and TNF-α also induce IL-6 in these cells; TNF-α but not IL-1α synergizes with OncM for IL-6 production. Immunoassay (IL-6 ELISA), Northern blot, receptor binding assay Journal of immunology Medium 1918953
1994 gp130 and LIF receptor β constitutively associate with JAK/TYK kinases (JAK1, JAK2, TYK2); ligand-induced dimerization of the receptor β components activates these kinases. The CNTF cytokine family receptors utilize all known members of the JAK-TYK family but induce distinct phosphorylation patterns. Co-immunoprecipitation, kinase activation assays Science High 8272873
1996 IL-6 induces VEGF expression in multiple cell lines (Northern blot); this induction is mediated not only by promoter DNA elements but also through specific motifs in the 5'-UTR of VEGF mRNA, suggesting IL-6 drives angiogenesis indirectly via VEGF induction. Northern blot analysis, transient transfection/reporter assays The Journal of biological chemistry High 8557680
1996 In vivo, the soluble IL-6 receptor (sIL-6R) dramatically hypersensitizes cells to IL-6 by prolonging IL-6 plasma half-life and extending the acute phase response; the IL-6/sIL-6R complex (but not IL-6 alone) drives massive extramedullary hematopoiesis in liver and spleen, demonstrating a biologically distinct activity of the trans-signaling complex. Transgenic mouse models expressing human IL-6, human sIL-6R, or both; acute-phase protein measurements; histology Immunology letters High 9052874
1999 Repression of the IL-6 gene in MCF-7 breast carcinoma cells is associated with hypermethylation of the IL-6 gene; treatment with 5-aza-2'-deoxycytidine (a demethylating agent) restores IL-6 expression, establishing DNA methylation as a mechanism of IL-6 transcriptional repression. Northern blot, 5-aza-dC treatment, methylation analysis Biochemical and biophysical research communications Medium 10329438
2000 IL-6 produced by contracting skeletal muscle accounts for the exercise-induced rise in plasma IL-6: direct arterial-femoral venous difference measurements showed net IL-6 release only from the exercising (not resting) leg, with IL-6 production rates of ~6.8 ng/min per kg active muscle. Arterial-femoral venous difference measurements, ultrasound Doppler blood flow, ELISA The Journal of physiology High 11080265
2001 During turpentine-induced inflammation, CRH is required for normal ACTH response and for adrenal IL-6 expression. Loss of CRH paradoxically increases plasma IL-6 from non-adrenal sources, revealing that IL-6 release during inflammation is CRH-dependent and IL-6 can compensate for CRH deficiency effects on food intake. Crh−/− and Crh−/−/IL-6−/− mouse models, ELISA, in situ hybridization The Journal of clinical investigation Medium 11602623
2002 IL-6 promotes Th2 differentiation by activating NFAT-mediated IL-4 transcription in naïve CD4+ T cells, while simultaneously inhibiting Th1 differentiation by upregulating SOCS-1 to interfere with IFNγ signaling — two independent molecular mechanisms. T cell differentiation assays, NFAT reporter assays, SOCS-1 expression analysis Molecular immunology Medium 12431386
2003 IL-6 induces anti-inflammatory responses in humans in vivo: recombinant IL-6 infusion (mimicking exercise levels, ~140 pg/mL) elevated plasma IL-1ra and IL-10, increased cortisol, and caused neutrocytosis and lymphopenia, without inducing TNF-α. Randomized human infusion study, ELISA cytokine measurements, leukocyte counts American journal of physiology. Endocrinology and metabolism High 12857678
2003 IL-6 induces insulin resistance in 3T3-L1 adipocytes through long-term inhibition of IRS-1, GLUT-4, and PPARγ gene transcription (reducing IRS-1 protein and insulin-stimulated glucose transport), without increasing pS-307 of IRS-1 or JNK activation (unlike TNF-α). Cell culture experiments with recombinant IL-6, Western blot, gene expression analysis, glucose transport assays The Journal of biological chemistry Medium 12952969
2004 IL-6 regulates in vivo dendritic cell differentiation through STAT3 activation via gp130: IL-6-knockout mice had increased mature DCs, and knockin mice with gp130 STAT3-signaling defects (gp130FxxQ/FxxQ) showed impaired IL-6-mediated suppression of LPS-induced DC maturation; STAT3 phosphorylation in DCs was regulated by IL-6 in vivo. IL-6 knockout and gp130 knockin mice, flow cytometry, T cell activation assays, STAT3 phosphorylation Journal of immunology High 15356132
2005 IL-6 directly inhibits primary hepatocyte proliferation via a p21cip1-dependent mechanism (loss of p21cip1 abolishes IL-6-mediated inhibition), while indirectly stimulating proliferation by inducing HGF production from non-parenchymal cells; SOCS3 negatively regulates these effects. Primary mouse hepatocyte culture, p21cip1-knockout cells, co-culture assays, SOCS3+/- mice, in vivo liver regeneration assay Biochemical and biophysical research communications High 16288983
2005 IL-6 rapidly increases AMPK activity in skeletal muscle, and IL-6-stimulated increases in fatty acid oxidation, basal/insulin-stimulated glucose uptake, and GLUT4 translocation to the plasma membrane are abrogated by dominant-negative AMPK, placing AMPK downstream of IL-6 signaling in muscle metabolism. IL-6 infusion/treatment of myotubes, AMPK activity assays, GLUT4 translocation, dominant-negative AMPK infection Biochemical Society transactions Medium 17956334
2006 IL-6 directly regulates hepcidin expression through induction of STAT3, which then binds the hepcidin promoter; STAT3 is both necessary and sufficient for the IL-6 responsiveness of the hepcidin promoter. STAT3 knockout/siRNA, promoter reporter assays, ChIP, ELISA Blood High 16835372
2006 Sleep enhances IL-6 trans-signaling capacity in healthy humans by selectively increasing concentrations of the proteolytically cleaved sIL-6R variant (not the differentially spliced form or mIL-6R density or sgp130), thus widening the spectrum of IL-6 target cells during sleep. Controlled sleep/wake study in humans, plasma sIL-6R/sgp130 measurement, mIL-6R flow cytometry, IL-6-producing monocyte analysis FASEB journal Medium 16912152
2009 Persistent DNA damage signaling (DSBs marked by γH2AX foci) triggers IL-6 secretion as part of the senescence-associated secretory phenotype (SASP); this requires the DDR proteins ATM, NBS1, and CHK2 (but not p53 or pRb), and ATM-dependent IL-6 promotes cancer cell invasiveness in a paracrine manner. shRNA knockdown of DDR proteins, IL-6 ELISA, invasion assays, immunofluorescence Nature cell biology High 19597488
2009 Transient Src oncoprotein activation triggers an NF-κB-mediated inflammatory circuit that directly activates Lin28, which reduces let-7 microRNA levels; let-7 directly represses IL-6 translation, so its loss leads to elevated IL-6, which activates STAT3; STAT3 is necessary for cell transformation, and IL-6 activates NF-κB completing a positive feedback loop maintaining stable transformation. shRNA, reporter assays, overexpression, miRNA inhibitors, STAT3 inhibition, mammosphere formation assays Cell High 19878981
2011 IL-6 classical signaling (via membrane-bound IL-6R → gp130 dimerization → JAK activation → SHP-2/Ras/MAPK and STAT3 phosphorylation → nuclear translocation) mediates regenerative/anti-inflammatory activities, while trans-signaling (via soluble IL-6R/gp130 complex) mediates pro-inflammatory responses. Review synthesizing biochemical pathway analysis; signaling domain experiments, chimeric receptor studies Biochimica et biophysica acta High 21296109
2011 IL-6 trans-signaling (via soluble IL-6R) activates STAT3/SOCS3 in pancreatic ductal cells, and this signaling is required for progression of KrasG12D-driven pancreatic intraepithelial neoplasias (PanINs) to pancreatic ductal adenocarcinoma; myeloid cells are the source of IL-6 that activates pancreatic STAT3. Genetic mouse models (Kras G12D; IL-6 trans-signaling deficient; Socs3 knockout), immunohistochemistry, STAT3 phosphorylation analysis Cancer cell High 21481788
2011 IL-6 stimulates GLP-1 secretion from intestinal L cells and pancreatic α cells; in α cells, IL-6 increases GLP-1 production by upregulating proglucagon and prohormone convertase 1/3 expression, thereby improving insulin secretion and glycemia. IL-6 administration in mice/humans, GLP-1 ELISA, proglucagon/PC1-3 mRNA and protein expression, in vitro L cell and α cell experiments Nature medicine High 22037645
2012 IL-6 combined with TGF-β synergistically promotes proteasome-dependent FOXP3 protein degradation (post-translational), reducing Treg activity; MG132 (proteasome inhibitor) blocked this effect; IL-6/TGF-β upregulated IL-6R expression without affecting FOXP3 mRNA stability. FOXP3 overexpression model, Western blot, proteasome inhibitor (MG132), flow cytometry International journal of clinical and experimental pathology Medium 22977658
2014 SOCS3 inhibits IL-6 signaling by binding simultaneously to gp130 and JAK1/JAK2/TYK2 (but not JAK3) via a 'GQM' motif in the JAK kinase domain; SOCS3 inhibits JAK activity in an ATP-independent manner by partially occluding the kinase substrate-binding groove with its kinase inhibitory region. Biochemical/structural studies, domain mutagenesis, binding assays Seminars in immunology High 24418198
2015 Tet2 selectively represses IL-6 transcription during inflammation resolution by recruiting Hdac2 to the Il6 promoter (independent of DNA methylation/hydroxymethylation); IκBζ targets Tet2 to the Il6 promoter; Tet2-deficient mice show elevated IL-6 and increased susceptibility to endotoxin shock and colitis. Tet2-knockout mice, ChIP assays, HDAC inhibitor experiments, Co-IP (Tet2-Hdac2), luciferase reporter assays Nature High 26287468
2017 IL-6 enhances osteocyte-mediated osteoclastogenesis by activating the JAK2-STAT3 pathway to upregulate RANKL expression in osteocyte-like MLO-Y4 cells; inhibition of JAK2 with AG490 suppressed pJAK2, RANKL expression, and osteoclast differentiation. RT-PCR, Western blot, TRAP staining/osteoclast formation assay, JAK2 inhibitor AG490 Cellular physiology and biochemistry Medium 28278513
2017 Kdm6a (demethylase) promotes IL-6 transcription in macrophages by demethylating H3K27me3 at the IL-6 promoter in an enzymatic activity-dependent manner; this activity is downregulated via JNK pathway upon innate stimuli. Kdm6a knockdown/overexpression, ChIP-seq, H3K27me3 ChIP, enzymatic activity mutants in primary macrophages Journal of autoimmunity Medium 28284523
2017 Post-MI cardiac IL-6 is preferentially produced by cardiac fibroblasts; adenosine stimulates fibroblast IL-6 formation via adenosine receptor A2bR in a Gq-dependent manner; cardiac fibroblasts degrade extracellular ATP to adenosine but lack CD73, relying on T cell-derived adenosine for IL-6 regulation. Single-cell RNA-seq (mouse and human), RNAscope, qPCR, protein quantification in isolated cell types, A2bR pharmacology, CD4-CD73-/- mouse model The Journal of clinical investigation High 36943408
2021 IL-6 activates autophagy through the IL-6/JAK2/BECN1 pathway: JAK2 directly phosphorylates BECN1 at Y333 upon IL-6 stimulation; Y333 phosphorylation is required for BECN1 activation and PI3KC3 complex formation, promoting chemotherapy resistance in colorectal cancer. Co-IP, in vitro kinase assay, site-directed mutagenesis (Y333), PI3KC3 complex immunoprecipitation, autophagy flux assays Nature communications High 34131122
2023 IL-6 induces Csf1r (CSF1R) expression in Tet2-deficient macrophages through enhanced STAT3 binding to the Csf1r promoter; IL-6 receptor antibody treatment reverses Tet2 clonal hematopoiesis-accelerated atherosclerosis by reducing monocytosis, lesional macrophage burden, and CSF1R expression. IL-6R antibody treatment in Tet2 CH mice, ChIP for STAT3 at Csf1r promoter, CSF1R inhibitor (PLX3397), mouse and human macrophage experiments Nature cardiovascular research High 37539077
2023 In M2 macrophages, YY1 forms a liquid-liquid phase separation complex with p300, p65, and CEBPB that upregulates IL-6 through long-range chromatin interactions between an M2-specific IL-6 enhancer and the IL-6 promoter; IL-4/STAT6 pathway regulates YY1 expression. CRISPR-Cas9 KO, H3K27ac-ChIP-seq, YY1 ChIP-seq, LLPS assays, chromatin conformation (enhancer-promoter interaction), RNA-seq Journal for immunotherapy of cancer High 37094986

Source papers

Stage 0 corpus · 130 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 3581 25190079
2011 The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochimica et biophysica acta 2469 21296109
2018 Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nature reviews. Clinical oncology 2427 29405201
2009 Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosomatic medicine 2179 19188531
1986 Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature 2129 3491322
2015 IL-6 as a keystone cytokine in health and disease. Nature immunology 1874 25898198
2009 Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nature cell biology 1754 19597488
1987 Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proceedings of the National Academy of Sciences of the United States of America 1737 2444978
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1989 Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell 1362 2788034
2002 Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nature medicine 1339 11984595
1990 Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell 1259 2261637
2009 An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell 1202 19878981
2003 Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes 1167 12606524
1994 Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. Science (New York, N.Y.) 929 8272873
1990 IL-6 is produced by osteoblasts and induces bone resorption. Journal of immunology (Baltimore, Md. : 1950) 925 2121824
1996 Interleukin 6 induces the expression of vascular endothelial growth factor. The Journal of biological chemistry 896 8557680
2012 Interleukin-6, a major cytokine in the central nervous system. International journal of biological sciences 850 23136554
2015 Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-α. Molecular psychiatry 836 26033244
2003 Chronic stress and age-related increases in the proinflammatory cytokine IL-6. Proceedings of the National Academy of Sciences of the United States of America 835 12840146
2003 Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. The Journal of biological chemistry 816 12952969
2003 IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. American journal of physiology. Endocrinology and metabolism 812 12857678
2000 Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6. The Journal of physiology 780 11080265
2004 Relationship of obesity and visceral adiposity with serum concentrations of CRP, TNF-alpha and IL-6. Diabetes research and clinical practice 773 15955385
2006 Interleukin-6 induces hepcidin expression through STAT3. Blood 759 16835372
2020 Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. The Journal of allergy and clinical immunology 736 32425269
2011 Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nature medicine 730 22037645
2005 IL-10, IL-6, and TNF-alpha: central factors in the altered cytokine network of uremia--the good, the bad, and the ugly. Kidney international 715 15780075
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