Pathway maps

Immune response_IL-6 signaling pathway
Immune response_IL-6 signaling pathway

Object List (links open in MetaCore):

c-Jun, JAK1, ADAM10, CREB1, IL-6 receptor, C/EBPbeta, c-Raf-1, MEK2, c-Jun, ERK1/2, IL-6, NF-KB, GCR-alpha, SHP-2, Elk-1, SOCS3, STAT3, c-Fos, IL6RA, Gp130, SOS, GRB2, junD, MEK1, C/EBPdelta, ADAM17, H-Ras, C/EBPbeta, Shc, SRF, c-Fos, PtdIns(3,4,5)P3


IL-6 signaling pathway

Interleukin-6 ( IL-6 ) is a pleiotropic cytokine produced by various types of lymphoid and nonlymphoid cells, such as T cells, B cells, monocytes, fibroblasts, keratinocytes, endothelial cells, mesangial cells and several tumor cells. IL-6 provokes a broad range of cellular and physiological responses, including the immune response, inflammation, hematopoiesis and oncogenesis by regulating cell growth, gene activation, proliferation, survival and differentiation [1].

IL-6 signals through IL-6 receptor composed of two different subunits, Interleukin 6 receptor alpha subunit ( IL6RA ) that produces ligand specificity and Interleukin 6 signal transducer ( gp130 ), a receptor subunit shared with other cytokines of the IL-6 family [2].

Binding of IL-6 to its receptor initiates cellular events including activation of Janus kinase 1 ( JAK1 )/ Signal transducer and activator of transcription 3 ( STAT3 ) and Extracellular signal-regulated kinase 1 and 2 ( ERK1/2 ) signaling pathways [3], [4], [5].

Activated JAK1 phosphorylates STAT3, which dimerizes and is translocated to the nucleus to activate transcription of genes containing STAT3 response elements [6], [7], [3].

Up-regulation of Suppressor of cytokine signaling 3 ( SOCS3 ) gene transcription by STAT3 leads to the termination of IL-6 cytokine signaling [8], [9], [10], [11].

JAK1 is also required for the tyrosine phosphorylation of Protein tyrosine phosphatase non-receptor type 11 ( SHP-2 ) that associates with SHC transforming protein 1 ( Shc ) and Growth factor receptor-bound protein 2 ( GRB2 ) followed by activation of the ERK1/2 signaling [12], [13], [14], [15], [4].

Shc/ GRB2/ Son of sevenless homologs ( SOS )/ v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras )/ v-Raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 )/ Mitogen-activated protein kinase kinase 1 and 2 ( MEK1 and MEK2 )/ ERK1/2 pathway activates transcription factors such as ELK1 member of ETS oncogene family ( Elk-1 ) and CCAAT/enhancer binding protein beta ( C/EBPbeta ) that act through their own cognate response elements in the genome [16], [17], [1], [18], [19], [20]. These factors and other transcription factors, including v-Fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos ), Jun oncogene ( c-Jun ) and Serum response factor ( SRF ) regulate a variety of complex promoters and enhancers that respond to IL-6 [21], [22], [23], [24], [25], [5].

c-Jun and c-Fos also cooperate with STAT3 in IL-6 -induced transactivation of target gene promoters containing IL-6 response element (IRE) [26], [27]. In turn, STAT3 can induce c-Fos gene expression in response to IL-6 [18].

IL-6 activates cells by binding to the membrane-bound IL6RA and subsequent formation of a complex with gp130 homodimer. Cells that express gp130, but not IL6RA, can be activated by IL-6 and the soluble IL6RA which is produced by shedding from the cell surface by metalloproteinases ADAM17 and ADAM10 [28], [29].

In response to a variety of signals, such as bacterial pathogens, Interleukin-1 beta (IL-1 beta), Tumor necrosis factor alpha (TNF-alpha), Transforming growth factor, beta 1 (TGF-beta 1) etc., IL-6 gene expression is up-regulated by a wide range of transcription factors, including Nuclear factor-kappa B ( NF-kB ), C/EBPbeta, CCAAT/enhancer binding protein delta ( C/EBPdelta ), cAMP responsive element binding protein 1 ( CREB1 ), Jun D proto-oncogene ( junD ), v-Fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos ), Jun oncogene ( c-Jun ), depending on cell type and ligand specificity [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41].

The feedback inhibition of IL-6 gene expression by glucocorticoids represents a regulatory link between the endocrine and immune systems. Ligand-activated Glucocorticoid receptor ( GCR-alpha ) represses the IL-6 gene transcription by occlusion not only of the inducible IL-6 enhancer region but also of the basal IL-6 promoter elements [42], [43].


  1. Naka T, Nishimoto N, Kishimoto T
    The paradigm of IL-6: from basic science to medicine. Arthritis research 2002;4 Suppl 3:S233-42
  2. Hirano T
    Interleukin 6 and its receptor: ten years later. International reviews of immunology 1998;16(3-4):249-84
  3. Murray PJ
    The JAK-STAT signaling pathway: input and output integration. Journal of immunology (Baltimore, Md. : 1950) 2007 Mar 1;178(5):2623-9
  4. Fischer P, Hilfiker-Kleiner D
    Survival pathways in hypertrophy and heart failure: the gp130-STAT axis. Basic research in cardiology 2007 Sep;102(5):393-411
  5. Fischer P, Hilfiker-Kleiner D
    Role of gp130-mediated signalling pathways in the heart and its impact on potential therapeutic aspects. British journal of pharmacology 2008 Mar;153 Suppl 1:S414-27
  6. Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, Graeve L
    Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. The Biochemical journal 1998 Sep 1;334 ( Pt 2):297-314
  7. Hirano T, Ishihara K, Hibi M
    Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene 2000 May 15;19(21):2548-56
  8. Pfitzner E, Kliem S, Baus D, Litterst CM
    The role of STATs in inflammation and inflammatory diseases. Current pharmaceutical design 2004;10(23):2839-50
  9. Lang R
    Tuning of macrophage responses by Stat3-inducing cytokines: molecular mechanisms and consequences in infection. Immunobiology 2005;210(2-4):63-76
  10. Zhang L, Badgwell DB, Bevers JJ 3rd, Schlessinger K, Murray PJ, Levy DE, Watowich SS
    IL-6 signaling via the STAT3/SOCS3 pathway: functional analysis of the conserved STAT3 N-domain. Molecular and cellular biochemistry 2006 Aug;288(1-2):179-89
  11. He HJ, Zhu TN, Xie Y, Fan J, Kole S, Saxena S, Bernier M
    Pyrrolidine Dithiocarbamate Inhibits Interleukin-6 Signaling through Impaired STAT3 Activation and Association with Transcriptional Coactivators in Hepatocytes. The Journal of biological chemistry 2006 Oct 20;281(42):31369-79
  12. Fukada T, Hibi M, Yamanaka Y, Takahashi-Tezuka M, Fujitani Y, Yamaguchi T, Nakajima K, Hirano T
    Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis. Immunity 1996 Nov;5(5):449-60
  13. Schaper F, Gendo C, Eck M, Schmitz J, Grimm C, Anhuf D, Kerr IM, Heinrich PC
    Activation of the protein tyrosine phosphatase SHP2 via the interleukin-6 signal transducing receptor protein gp130 requires tyrosine kinase Jak1 and limits acute-phase protein expression. The Biochemical journal 1998 Nov 1;335 ( Pt 3):557-65
  14. Kim H, Baumann H
    Dual signaling role of the protein tyrosine phosphatase SHP-2 in regulating expression of acute-phase plasma proteins by interleukin-6 cytokine receptors in hepatic cells. Molecular and cellular biology 1999 Aug;19(8):5326-38
  15. Cronstein BN
    Interleukin-6--a key mediator of systemic and local symptoms in rheumatoid arthritis. Bulletin of the NYU hospital for joint diseases 2007;65 Suppl 1:S11-5
  16. Kumar G, Gupta S, Wang S, Nel AE
    Involvement of Janus kinases, p52shc, Raf-1, and MEK-1 in the IL-6-induced mitogen-activated protein kinase cascade of a growth-responsive B cell line. Journal of immunology (Baltimore, Md. : 1950) 1994 Nov 15;153(10):4436-47
  17. Morgan K, Scobie G, Marsters P, Kalsheker NA
    Mutation in an alpha1-antitrypsin enhancer results in an interleukin-6 deficient acute-phase response due to loss of cooperativity between transcription factors. Biochimica et biophysica acta 1997 Nov 28;1362(1):67-76
  18. Yang E, Lerner L, Besser D, Darnell JE Jr
    Independent and cooperative activation of chromosomal c-fos promoter by STAT3. The Journal of biological chemistry 2003 May 2;278(18):15794-9
  19. Bannach FG, Gutierrez-Fernandez A, Parmer RJ, Miles LA
    Interleukin-6-induced plasminogen gene expression in murine hepatocytes is mediated by transcription factor CCAAT/enhancer binding protein beta (C/EBPbeta). Journal of thrombosis and haemostasis : JTH 2004 Dec;2(12):2205-12
  20. Young DP, Kushner I, Samols D
    Binding of C/EBPbeta to the C-reactive protein (CRP) promoter in Hep3B cells is associated with transcription of CRP mRNA. Journal of immunology (Baltimore, Md. : 1950) 2008 Aug 15;181(4):2420-7
  21. Agrawal A, Cha-Molstad H, Samols D, Kushner I
    Overexpressed nuclear factor-kappaB can participate in endogenous C-reactive protein induction, and enhances the effects of C/EBPbeta and signal transducer and activator of transcription-3. Immunology 2003 Apr;108(4):539-47
  22. Kamimura D, Ishihara K, Hirano T
    IL-6 signal transduction and its physiological roles: the signal orchestration model. Reviews of physiology, biochemistry and pharmacology. 2003;149:1-38
  23. Higashi N, Kunimoto H, Kaneko S, Sasaki T, Ishii M, Kojima H, Nakajima K
    Cytoplasmic c-Fos induced by the YXXQ-derived STAT3 signal requires the co-operative MEK/ERK signal for its nuclear translocation. Genes to cells : devoted to molecular & cellular mechanisms 2004 Mar;9(3):233-42
  24. Pradervand S, Yasukawa H, Muller OG, Kjekshus H, Nakamura T, St Amand TR, Yajima T, Matsumura K, Duplain H, Iwatate M, Woodard S, Pedrazzini T, Ross J, Firsov D, Rossier BC, Hoshijima M, Chien KR
    Small proline-rich protein 1A is a gp130 pathway- and stress-inducible cardioprotective protein. The EMBO journal 2004 Nov 10;23(22):4517-25
  25. Fischer P, Hilfiker-Kleiner D
    Survival pathways in hypertrophy and heart failure: the gp130-STAT3 axis. Basic research in cardiology 2007 Jul;102(4):279-97
  26. Schuringa JJ, Timmer H, Luttickhuizen D, Vellenga E, Kruijer W
    c-Jun and c-Fos cooperate with STAT3 in IL-6-induced transactivation of the IL-6 respone element (IRE). Cytokine 2001 Apr 21;14(2):78-87
  27. Ginsberg M, Czeko E, Muller P, Ren Z, Chen X, Darnell JE Jr
    Amino acid residues required for physical and cooperative transcriptional interaction of STAT3 and AP-1 proteins (cJun, cFos). Molecular and cellular biology 2007 Jul 16;
  28. Matthews V, Schuster B, Schutze S, Bussmeyer I, Ludwig A, Hundhausen C, Sadowski T, Saftig P, Hartmann D, Kallen KJ, Rose-John S
    Cellular cholesterol depletion triggers shedding of the human interleukin-6 receptor by ADAM10 and ADAM17 (TACE). The Journal of biological chemistry 2003 Oct 3;278(40):38829-39
  29. Huovila AP, Turner AJ, Pelto-Huikko M, Karkkainen I, Ortiz RM
    Shedding light on ADAM metalloproteinases. Trends in biochemical sciences 2005 Jul;30(7):413-22
  30. Akira S, Isshiki H, Sugita T, Tanabe O, Kinoshita S, Nishio Y, Nakajima T, Hirano T, Kishimoto T
    A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family. The EMBO journal 1990 Jun;9(6):1897-906
  31. Miyazawa K, Mori A, Yamamoto K, Okudaira H
    Transcriptional roles of CCAAT/enhancer binding protein-beta, nuclear factor-kappaB, and C-promoter binding factor 1 in interleukin (IL)-1beta-induced IL-6 synthesis by human rheumatoid fibroblast-like synoviocytes. The Journal of biological chemistry 1998 Mar 27;273(13):7620-7
  32. Tuyt LM, Dokter WH, Birkenkamp K, Koopmans SB, Lummen C, Kruijer W, Vellenga E
    Extracellular-regulated kinase 1/2, Jun N-terminal kinase, and c-Jun are involved in NF-kappa B-dependent IL-6 expression in human monocytes. Journal of immunology (Baltimore, Md. : 1950) 1999 Apr 15;162(8):4893-902
  33. Hungness ES, Pritts TA, Luo GJ, Sun X, Penner CG, Hasselgren PO
    The transcription factor activator protein-1 is activated and interleukin-6 production is increased in interleukin-1beta-stimulated human enterocytes. Shock (Augusta, Ga.) 2000 Sep;14(3):386-91
  34. Hungness ES, Luo GJ, Pritts TA, Sun X, Robb BW, Hershko D, Hasselgren PO
    Transcription factors C/EBP-beta and -delta regulate IL-6 production in IL-1beta-stimulated human enterocytes. Journal of cellular physiology 2002 Jul;192(1):64-70
  35. Hershko DD, Robb BW, Luo G, Hasselgren PO
    Multiple transcription factors regulating the IL-6 gene are activated by cAMP in cultured Caco-2 cells. American journal of physiology. Regulatory, integrative and comparative physiology. 2002 Nov;283(5):R1140-8
  36. Park JI, Lee MG, Cho K, Park BJ, Chae KS, Byun DS, Ryu BK, Park YK, Chi SG
    Transforming growth factor-beta1 activates interleukin-6 expression in prostate cancer cells through the synergistic collaboration of the Smad2, p38-NF-kappaB, JNK, and Ras signaling pathways. Oncogene 2003 Jul 10;22(28):4314-32
  37. Yamamoto M, Yamazaki S, Uematsu S, Sato S, Hemmi H, Hoshino K, Kaisho T, Kuwata H, Takeuchi O, Takeshige K, Saitoh T, Yamaoka S, Yamamoto N, Yamamoto S, Muta T, Takeda K, Akira S
    Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IkappaBzeta. Nature 2004 Jul 8;430(6996):218-22
  38. Xiao W, Hodge DR, Wang L, Yang X, Zhang X, Farrar WL
    Co-operative functions between nuclear factors NFkappaB and CCAT/enhancer-binding protein-beta (C/EBP-beta) regulate the IL-6 promoter in autocrine human prostate cancer cells. The Prostate 2004 Dec 1;61(4):354-70
  39. Lu H, Wu JY, Kudo T, Ohno T, Graham DY, Yamaoka Y
    Regulation of interleukin-6 promoter activation in gastric epithelial cells infected with Helicobacter pylori. Molecular biology of the cell 2005 Oct;16(10):4954-66
  40. Persson E, Voznesensky OS, Huang YF, Lerner UH
    Increased expression of interleukin-6 by vasoactive intestinal peptide is associated with regulation of CREB, AP-1 and C/EBP, but not NF-kappaB, in mouse calvarial osteoblasts. Bone 2005 Oct;37(4):513-29
  41. Spooner CJ, Guo X, Johnson PF, Schwartz RC
    Differential roles of C/EBP beta regulatory domains in specifying MCP-1 and IL-6 transcription. Molecular immunology 2007 Feb;44(6):1384-92
  42. Ray A, LaForge KS, Sehgal PB
    On the mechanism for efficient repression of the interleukin-6 promoter by glucocorticoids: enhancer, TATA box, and RNA start site (Inr motif) occlusion. Molecular and cellular biology 1990 Nov;10(11):5736-46
  43. Hayashi R, Wada H, Ito K, Adcock IM
    Effects of glucocorticoids on gene transcription. European journal of pharmacology 2004 Oct 1;500(1-3):51-62