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Gene Review

Il6  -  interleukin 6

Mus musculus

Synonyms: B-cell hybridoma growth factor, IL-6, Il-6, Interleukin HP-1, Interleukin-6
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Disease relevance of Il6


Psychiatry related information on Il6

  • Although a considerable amount of evidence has shown that physical and psychological stress elevates the plasma interleukin 6 (IL-6) levels, the physiological significance of such an elevation remains to be elucidated [10].
  • The 10 d stress time studies indicate that increased IL-6 secretion is positively related to elevated iSP in the peritoneal wash fluid and inversely related to reduced iSP in certain peritoneum-containing tissues [11].
  • Increased levels of interleukin-6 (IL-6) have been proposed to contribute to a number of pathological disorders, including osteoporosis and Alzheimer's disease [12].
  • IL-6-deficient animals showed higher locomotor activity in an open field and lower levels of exploration of the open arms of the elevated plus maze than control animals [13].
  • Sleep-wake behavior and responses of interleukin-6-deficient mice to sleep deprivation [14].

High impact information on Il6


Chemical compound and disease context of Il6


Genetic context of IL-6




Biological context of Il6


Anatomical context of Il6


Associations of Il6 with chemical compounds

  • MEKK3 forms a complex with TRAF6 in response to IL-1 and lipopolysaccharide (LPS) but not CpG, and is required for IL-1R- and TLR4-induced IL-6 production [33].
  • In vivo, the administration of PGE2 before LPS challenge significantly reduces circulating TNF-alpha and IL-6 levels [34].
  • We also show that corticosterone is normally induced in IL-6-deficient mice, demonstrating that IL-6 is not required for the activation of the hypothalamic-pituitary-adrenal axis [35].
  • A second alteration involved impaired de novo synthesis of C3 both in serum and germinal center cells from IL-6-deficient mice [26].
  • In a dose-dependent manner, PGE2 inhibits LPS-induced release of TNF-alpha and IL-6, but not of lactate or nitric oxide [34].
  • We further dissected a signalling pathway regulating Plasmodium-induced expression of IL-6 by DCs, which is mediated by release of PGE2, increases in intracellular cAMP and activation of PKA and p38-MAPK [36].

Physical interactions of Il6

  • Luciferase reporter constructs with alterations in presumptive cis-acting transcriptional regulatory elements demonstrate that the cyclic AMP-response element and two nuclear factor interleukin-6 (CCAAT/enhancer-binding protein (C/EBP)) sites of the COX-2 promoter are required for optimal endotoxin-dependent induction [37].
  • Mutation within the AP-1-binding site in the IL-6 promoter diminished the effect of CO on promoter activity, and treatment of macrophages with CO decreased AP-1 binding in an electrophoretic mobility shift assay [38].
  • Expression of IL-6 mRNA is known to be dependent upon NF kappa B that binds to the 5'-flanking region of the IL-6 gene [39].
  • Binding data and Scatchard analysis support these results and show an increase from 3100 to 17,620 low-affinity IL-2 binding sites per cell without any change in affinity after induction of M1 cells by the combination of IL-6 and IL-1 [40].
  • A model of the Ig-like domain showed that the binding site is very similar to the viral interleukin-6 binding site (site III) on the Ig-like domain of gp130, a related receptor [41].

Enzymatic interactions of Il6

  • LPS stimulation in gp130-deleted and also IL6 -/- animals after PH leads to a significant reduction in survival and DNA synthesis, which was associated with decreased Bcl-xL expression and higher apoptosis in the liver [42].

Regulatory relationships of Il6


Other interactions of Il6


Analytical, diagnostic and therapeutic context of Il6


  1. Hepatocellular proliferation in response to a peroxisome proliferator does not require TNFalpha signaling. Anderson, S.P., Dunn, C.S., Cattley, R.C., Corton, J.C. Carcinogenesis (2001) [Pubmed]
  2. Impaired immune and acute-phase responses in interleukin-6-deficient mice. Kopf, M., Baumann, H., Freer, G., Freudenberg, M., Lamers, M., Kishimoto, T., Zinkernagel, R., Bluethmann, H., Köhler, G. Nature (1994) [Pubmed]
  3. Interleukin-6-deficient mice develop mature-onset obesity. Wallenius, V., Wallenius, K., Ahrén, B., Rudling, M., Carlsten, H., Dickson, S.L., Ohlsson, C., Jansson, J.O. Nat. Med. (2002) [Pubmed]
  4. T cell growth and differentiation induced by interleukin-HP1/IL-6, the murine hybridoma/plasmacytoma growth factor. Uyttenhove, C., Coulie, P.G., Van Snick, J. J. Exp. Med. (1988) [Pubmed]
  5. Interleukin 6 is required for the development of collagen-induced arthritis. Alonzi, T., Fattori, E., Lazzaro, D., Costa, P., Probert, L., Kollias, G., De Benedetti, F., Poli, V., Ciliberto, G. J. Exp. Med. (1998) [Pubmed]
  6. Classic interleukin-6 receptor signaling and interleukin-6 trans-signaling differentially control angiotensin II-dependent hypertension, cardiac signal transducer and activator of transcription-3 activation, and vascular hypertrophy in vivo. Coles, B., Fielding, C.A., Rose-John, S., Scheller, J., Jones, S.A., O'Donnell, V.B. Am. J. Pathol. (2007) [Pubmed]
  7. Interleukin-6 receptor-mediated activation of signal transducer and activator of transcription-3 (STAT3) promotes choroidal neovascularization. Izumi-Nagai, K., Nagai, N., Ozawa, Y., Mihara, M., Ohsugi, Y., Kurihara, T., Koto, T., Satofuka, S., Inoue, M., Tsubota, K., Okano, H., Oike, Y., Ishida, S. Am. J. Pathol. (2007) [Pubmed]
  8. Ambient particulate matter accelerates coagulation via an IL-6-dependent pathway. Mutlu, G.M., Green, D., Bellmeyer, A., Baker, C.M., Burgess, Z., Rajamannan, N., Christman, J.W., Foiles, N., Kamp, D.W., Ghio, A.J., Chandel, N.S., Dean, D.A., Sznajder, J.I., Budinger, G.R. J. Clin. Invest. (2007) [Pubmed]
  9. Therapeutic effects of interleukin-6 blockade in a murine model of polymyositis that does not require interleukin-17A. Okiyama, N., Sugihara, T., Iwakura, Y., Yokozeki, H., Miyasaka, N., Kohsaka, H. Arthritis Rheum. (2009) [Pubmed]
  10. The restraint stress-induced elevation in plasma interleukin-6 negatively regulates the plasma TNF-alpha level. Nukina, H., Sudo, N., Komaki, G., Yu, X., Mine, K., Kubo, C. Neuroimmunomodulation (1998) [Pubmed]
  11. Endogenous substance P mediates cold water stress-induced increase in interleukin-6 secretion from peritoneal macrophages. Zhu, G.F., Chancellor-Freeland, C., Berman, A.S., Kage, R., Leeman, S.E., Beller, D.I., Black, P.H. J. Neurosci. (1996) [Pubmed]
  12. Expression of interleukin-6 in atherosclerotic lesions of male ApoE-knockout mice: inhibition by 17beta-estradiol. Sukovich, D.A., Kauser, K., Shirley, F.D., DelVecchio, V., Halks-Miller, M., Rubanyi, G.M. Arterioscler. Thromb. Vasc. Biol. (1998) [Pubmed]
  13. The role of interleukin-6 in stress-induced hyperthermia and emotional behaviour in mice. Butterweck, V., Prinz, S., Schwaninger, M. Behav. Brain Res. (2003) [Pubmed]
  14. Sleep-wake behavior and responses of interleukin-6-deficient mice to sleep deprivation. Morrow, J.D., Opp, M.R. Brain Behav. Immun. (2005) [Pubmed]
  15. AID is required for c-myc/IgH chromosome translocations in vivo. Ramiro, A.R., Jankovic, M., Eisenreich, T., Difilippantonio, S., Chen-Kiang, S., Muramatsu, M., Honjo, T., Nussenzweig, A., Nussenzweig, M.C. Cell (2004) [Pubmed]
  16. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Lock, C., Hermans, G., Pedotti, R., Brendolan, A., Schadt, E., Garren, H., Langer-Gould, A., Strober, S., Cannella, B., Allard, J., Klonowski, P., Austin, A., Lad, N., Kaminski, N., Galli, S.J., Oksenberg, J.R., Raine, C.S., Heller, R., Steinman, L. Nat. Med. (2002) [Pubmed]
  17. MLN120B, a Novel I{kappa}B Kinase {beta} Inhibitor, Blocks Multiple Myeloma Cell Growth In vitro and In vivo. Hideshima, T., Neri, P., Tassone, P., Yasui, H., Ishitsuka, K., Raje, N., Chauhan, D., Podar, K., Mitsiades, C., Dang, L., Munshi, N., Richardson, P., Schenkein, D., Anderson, K.C. Clin. Cancer Res. (2006) [Pubmed]
  18. Interleukin-6 is a needed proinflammatory cytokine in the prolonged neural activity and transcriptional activation of corticotropin-releasing factor during endotoxemia. Vallières, L., Rivest, S. Endocrinology (1999) [Pubmed]
  19. Tumor necrosis factor alpha, interleukin-1 alpha, interleukin-6, and prostaglandin E2 production in murine peritoneal macrophages infected with Ehrlichia risticii. van Heeckeren, A.M., Rikihisa, Y., Park, J., Fertel, R. Infect. Immun. (1993) [Pubmed]
  20. Role of interleukin-6 in cardiomyocyte/cardiac fibroblast interactions during myocyte hypertrophy and fibroblast proliferation. Fredj, S., Bescond, J., Louault, C., Delwail, A., Lecron, J.C., Potreau, D. J. Cell. Physiol. (2005) [Pubmed]
  21. Inverse regulation of interleukin-6 (IL-6) and IL-6 receptor in histamine deficient histidine decarboxylase-knock-out mice. Horváth, B.V., Falus, A., Tóth, S., Szalai, C., Lázár-Molnár, E., Holub, M.C., Buzás, E., Nagy, A., Fulop, A.K. Immunol. Lett. (2002) [Pubmed]
  22. Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice. Franckhauser, S., Elias, I., Rotter Sopasakis, V., Ferré, T., Nagaev, I., Andersson, C.X., Agudo, J., Ruberte, J., Bosch, F., Smith, U. Diabetologia (2008) [Pubmed]
  23. Genetics of susceptibility to leishmaniasis in mice: four novel loci and functional heterogeneity of gene effects. Havelková, H., Badalová, J., Svobodová, M., Vojtíková, J., Kurey, I., Vladimirov, V., Demant, P., Lipoldová, M. Genes. Immun. (2006) [Pubmed]
  24. Priming of mouse macrophages with the macrophage colony-stimulating factor (CSF-1) induces a variety of pathways that regulate expression of the interleukin 6 (Il6) and granulocyte-macrophage colony-stimulating factor (Csfgm) genes. Kamdar, S.J., Fuller, J.A., Nishikawa, S.I., Evans, R. Exp. Cell Res. (1997) [Pubmed]
  25. SOCS3 regulates the plasticity of gp130 signaling. Lang, R., Pauleau, A.L., Parganas, E., Takahashi, Y., Mages, J., Ihle, J.N., Rutschman, R., Murray, P.J. Nat. Immunol. (2003) [Pubmed]
  26. Interleukin 6 influences germinal center development and antibody production via a contribution of C3 complement component. Kopf, M., Herren, S., Wiles, M.V., Pepys, M.B., Kosco-Vilbois, M.H. J. Exp. Med. (1998) [Pubmed]
  27. Accelerated Nerve Regeneration in Mice by upregulated expression of interleukin (IL) 6 and IL-6 receptor after trauma. Hirota, H., Kiyama, H., Kishimoto, T., Taga, T. J. Exp. Med. (1996) [Pubmed]
  28. Corticotropin-releasing hormone regulates IL-6 expression during inflammation. Venihaki, M., Dikkes, P., Carrigan, A., Karalis, K.P. J. Clin. Invest. (2001) [Pubmed]
  29. CSF-1 regulation of Il6 gene expression by murine macrophages: a pivotal role for GM-CSF. Evans, R., Shultz, L.D., Dranoff, G., Fuller, J.A., Kamdar, S.J. J. Leukoc. Biol. (1998) [Pubmed]
  30. Central role of IL-6 receptor signal-transducing chain gp130 in activation of L-selectin adhesion by fever-range thermal stress. Chen, Q., Wang, W.C., Bruce, R., Li, H., Schleider, D.M., Mulbury, M.J., Bain, M.D., Wallace, P.K., Baumann, H., Evans, S.S. Immunity (2004) [Pubmed]
  31. Activation-induced inhibition of interleukin 6-mediated T cell survival and signal transducer and activator of transcription 1 signaling. Teague, T.K., Schaefer, B.C., Hildeman, D., Bender, J., Mitchell, T., Kappler, J.W., Marrack, P. J. Exp. Med. (2000) [Pubmed]
  32. Interleukin 3-dependent and -independent mast cells stimulated with IgE and antigen express multiple cytokines. Burd, P.R., Rogers, H.W., Gordon, J.R., Martin, C.A., Jayaraman, S., Wilson, S.D., Dvorak, A.M., Galli, S.J., Dorf, M.E. J. Exp. Med. (1989) [Pubmed]
  33. Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3. Huang, Q., Yang, J., Lin, Y., Walker, C., Cheng, J., Liu, Z.G., Su, B. Nat. Immunol. (2004) [Pubmed]
  34. Evidence for the involvement of interleukin 10 in the differential deactivation of murine peritoneal macrophages by prostaglandin E2. Strassmann, G., Patil-Koota, V., Finkelman, F., Fong, M., Kambayashi, T. J. Exp. Med. (1994) [Pubmed]
  35. Defective inflammatory response in interleukin 6-deficient mice. Fattori, E., Cappelletti, M., Costa, P., Sellitto, C., Cantoni, L., Carelli, M., Faggioni, R., Fantuzzi, G., Ghezzi, P., Poli, V. J. Exp. Med. (1994) [Pubmed]
  36. Transcriptome profile of dendritic cells during malaria: cAMP regulation of IL-6. Carapau, D., Kruhofer, M., Chatalbash, A., Orengo, J.M., Mota, M.M., Rodriguez, A. Cell. Microbiol. (2007) [Pubmed]
  37. Transcriptional activation of the cyclooxygenase-2 gene in endotoxin-treated RAW 264.7 macrophages. Wadleigh, D.J., Reddy, S.T., Kopp, E., Ghosh, S., Herschman, H.R. J. Biol. Chem. (2000) [Pubmed]
  38. Suppression of inflammatory cytokine production by carbon monoxide involves the JNK pathway and AP-1. Morse, D., Pischke, S.E., Zhou, Z., Davis, R.J., Flavell, R.A., Loop, T., Otterbein, S.L., Otterbein, L.E., Choi, A.M. J. Biol. Chem. (2003) [Pubmed]
  39. Inhibition by N-acetyl-L-cysteine of interleukin-6 mRNA induction and activation of NF kappa B by tumor necrosis factor alpha in a mouse fibroblastic cell line, Balb/3T3. Shibanuma, M., Kuroki, T., Nose, K. FEBS Lett. (1994) [Pubmed]
  40. Interleukin 1 augments the expression of the interleukin 2 receptor alpha-chain in interleukin 6-stimulated myeloid cells by a transcriptional and posttranscriptional mechanism. Ruhl, S., Schwabe, M., Pluznik, D.H. Exp. Hematol. (1992) [Pubmed]
  41. Identification of ligand-binding site III on the immunoglobulin-like domain of the granulocyte colony-stimulating factor receptor. Layton, J.E., Hall, N.E., Connell, F., Venhorst, J., Treutlein, H.R. J. Biol. Chem. (2001) [Pubmed]
  42. Interleukin-6/glycoprotein 130-dependent pathways are protective during liver regeneration. Wuestefeld, T., Klein, C., Streetz, K.L., Betz, U., Lauber, J., Buer, J., Manns, M.P., Müller, W., Trautwein, C. J. Biol. Chem. (2003) [Pubmed]
  43. SOCS3 negatively regulates IL-6 signaling in vivo. Croker, B.A., Krebs, D.L., Zhang, J.G., Wormald, S., Willson, T.A., Stanley, E.G., Robb, L., Greenhalgh, C.J., Förster, I., Clausen, B.E., Nicola, N.A., Metcalf, D., Hilton, D.J., Roberts, A.W., Alexander, W.S. Nat. Immunol. (2003) [Pubmed]
  44. Interferon-gamma antagonizes interleukin-6-induced expression of interleukin-4 receptors in murine myeloid cells by a transcriptional mechanism. Ruhl, S., Feldman, G.M., Akahane, K., Pluznik, D.H. Blood (1993) [Pubmed]
  45. Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme. Kuida, K., Lippke, J.A., Ku, G., Harding, M.W., Livingston, D.J., Su, M.S., Flavell, R.A. Science (1995) [Pubmed]
  46. Lack of gp130 expression in hepatocytes promotes liver injury. Streetz, K.L., Wüstefeld, T., Klein, C., Kallen, K.J., Tronche, F., Betz, U.A., Schütz, G., Manns, M.P., Müller, W., Trautwein, C. Gastroenterology (2003) [Pubmed]
  47. IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Yasukawa, H., Ohishi, M., Mori, H., Murakami, M., Chinen, T., Aki, D., Hanada, T., Takeda, K., Akira, S., Hoshijima, M., Hirano, T., Chien, K.R., Yoshimura, A. Nat. Immunol. (2003) [Pubmed]
  48. Distinct contribution of IL-6, TNF-alpha, IL-1, and IL-10 to T cell-mediated spontaneous autoimmune arthritis in mice. Hata, H., Sakaguchi, N., Yoshitomi, H., Iwakura, Y., Sekikawa, K., Azuma, Y., Kanai, C., Moriizumi, E., Nomura, T., Nakamura, T., Sakaguchi, S. J. Clin. Invest. (2004) [Pubmed]
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