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IL-6 Pathway

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IL-6 (Interleukin-6) is a cytokine that 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. IL-6 signals through a receptor composed of two different subunits, an alpha subunit that produces ligand specificity and GP (Glycoprotein) 130, a receptor subunit shared in common with 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] (Ref.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 cytokine receptor to the Ras/MAP (Mitogen-Activated Protein) kinase pathway and is essential for mitogenic activity (Ref.2).

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 (Ref.3).

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 as 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 the 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 (Ref.4). 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).

References:
  1. Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, Graeve L
    Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway.
    Biochem J 1998 Sep 1;334 ( Pt 2):297-314.
  2. 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.
  3. Ichiba M, Nakajima K, Yamanaka Y, Kiuchi N, Hirano T
    Autoregulation of the Stat3 gene through cooperation with a cAMP-responsive element-binding protein.
    J Biol Chem 1998 Mar 13;273(11):6132-8.
  4. Chan D
    Specific inhibition of Stat3 signal transduction by PIAS3.
    Science. 1997 Dec 5;278(5344):1803-5.