IL-6 (Interleukin-6) is a pleiotropic cytokine that not only affects the immune system, but also acts in other biological systems and many physiological events in various organs, including inflammation, hematopoiesis, and oncogenesis by regulating cell growth, as well as gene activation, proliferation, survival, and differentiation. This protein signals through a receptor composed of two different subunits, an alpha subunit that produces ligand specificity and GP (Glycoprotein) 130, a receptor subunit shared by other cytokines in the IL-6 family. Binding of IL-6 to its receptor initiates cellular events including activation of JAK (Janus Kinase) kinases and activation of Ras-mediated signaling. Activated JAK kinases phosphorylate and activate STAT transcription factors, particularly STAT3 (Signal Transducers and Activators of Transcription-3) and SHP2 [SH2 (Src Homology-2) Domain-containing Tyrosine Phosphatase] [1]. Phosphorylated STAT3 then forms a dimer and translocates into the nucleus to activate transcription of genes containing STAT3 response elements. STAT3 is essential for GP130-mediated cell survival and G1 to S cell-cycle-transition signals. Both c-Myc and Pim have been identified as target genes of STAT3 and together can compensate for STAT3 in cell survival and cell-cycle transition. SHP2 links the cytokine receptor to the Ras/MAP (Mitogen-Activated Protein) kinase pathway and is essential for mitogenic activity [2,3].

The Ras-mediated pathway, acting through SHC, GRB2 (Growth Factor Receptor Bound protein-2), and SOS1 (Son of Sevenless-1) upstream and activating MAP kinases downstream, activates transcription factors such as Elk1 and NF-IL-6 (C/EBP-Beta) that can act through their own cognate response elements in the genome. These factors and other transcription factors like Activating Protein-1 and SRF (Serum Response Factor) that respond to many different signaling pathways come together to regulate a variety of complex promoters and enhancers that respond to IL-6 and other signaling factors [4]. In addition to JAK/STAT and Ras/MAP kinase pathways, IL-6 also activates PI3K (Phosphoinositide-3 Kinase). The PI3K/Akt/NF-KappaB cascade activated by IL-6, functions cooperatively to achieve the maximal anti-apoptotic effect of IL-6 against TGF-Beta (Transforming Growth Factor-Beta). The anti-apoptotic mechanism of PI3K/Akt is attributed to phosphorylation of the BCL2 (B-Cell Leukemia-2) family member BAD (BCL2 Associated Death Promoter) by Akt. The phosphorylated BAD is then associated with 14-3-3, which sequesters BAD from BCLXL, thereby promoting cell survival. Regulating the BCL2 family member is also considered one of the anti-apoptotic mechanisms of STAT3, which was reported to be capable of inducing BCL2 in pro-B cells. Thus, both anti-apoptotic signaling pathways transduced by IL-6 are likely to converge to BCL2 family members, which could act upstream of Caspase3. IL-6 also blocks the TGF-Beta induced activation of Caspase3. In addition to induction of BCL2, STAT3 can directly up-regulate the transcription of p21, which is implicated in anti-apoptosis. The termination of the IL-6-type cytokine signaling is through the action of tyrosine phosphatases, proteasome, and JAK kinase inhibitors SOCS (Suppressor of Cytokine Signaling), PIAS (Protein Inhibitors of Activated STATs), and internalization of the cytokine receptors via GP130. One of the major actions of IL-6 is the transcriptional activation of APP (Acute-Phase Plasma Proteins) genes in liver cells. SHP2 acts as a negative regulator of the JAK/STAT signaling in part by downregulating JAK activity, thereby indirectly moderating the induction of STAT3-dependent APP genes. IL-6 stimulates several types of leukocytes and the production of acute phase proteins in the liver. It is particularly important in inducing B-cells to differentiate into antibody-forming cells (plasma cells). IL-6 is released into the circulation, where it works in a hormone-like fashion to induce lipolysis and fat oxidation. In more recent experiments, it has been shown that IL-6 infusion increases glucose disposal during a hyperinsulinaemic euglycaemic clamp in healthy humans. IL-6 treatment of myotubes increases fatty acid oxidation, basal and insulin-stimulated glucose uptake, and translocation of GLUT4 to the plasma membrane. Furthermore, IL-6 rapidly and markedly increases AMPK (AMP-activated protein kinase) and the metabolic effects of IL-6 were abrogated in AMPK dominant negative-infected cells. Finally, IL-6 mediates anti-inflammatory effects by stimulating the production of anti-inflammatory cytokines and by suppressing TNFα production. We suggest that IL-6 and other muscle-derived cytokines (myokines) may play a role in preventing Type 2 diabetes [4,5,6].


Pathway

IL-6 Pathway

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Pathway Key

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References
  1. Ni CW, Hsieh HJ, Chao YJ, et al. (2004) Interleukin-6-induced JAK2/STAT3 signaling pathway in endothelial cells is suppressed by hemodynamic flow. Am J Physiol Cell Physiol 287(3):C771-80. Epub 2004 May 19.
  2. Schust J, Sperl B, Hollis A, et al. (2006) Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chem Biol 13(11):1235-42.
  3. Liang S, Ristich V, Arase H, et al. (2008) Modulation of dendritic cell differentiation by HLA-G and ILT4 requires the IL-6--STAT3 signaling pathway. Proc Natl Acad Sci U S A 105(24):8357-62. Epub 2008 Jun 11.
  4. Barry SP, Davidson SM, Townsend PA (2008) Molecular regulation of cardiac hypertrophy. Int J Biochem Cell Biol 40(10):2023-39. Epub 2008 Feb 26. Review.
  5. Yagil Z, Nechushtan H, Kay G, et al. (2010) The enigma of the role of protein inhibitor of activated STAT3 (PIAS3) in the immune response. Trends Immunol 31(5):199-204. Epub 2010 Feb 22. Review.
  6. Pedersen BK (2007) IL-6 signalling in exercise and disease. Biochem Soc Trans 35(Pt 5):1295-7. Review.