How IL-6 Signaling Works

For U.S. Healthcare Professionals Only

IL-6 signals through 2 distinct mechanisms1-7

  • Interleukin-6 (IL-6) can signal through membrane-bound receptors (classical or cis-signaling)

  • IL-6 can also signal through soluble forms of its receptors (trans-signaling)

  • These 2 distinct signaling mechanisms allow IL-6 to interact with cells that express the IL-6 membrane-bound receptor (mIL-6R), as well as with cells that do not

IL-6 signals through classical signaling and trans-signaling1-7

The presence of both membrane-bound and soluble receptors gives IL-6 an expanded range of biological activities, allowing it to interact with a wide array of cells and tissues.1,7,9,14-19

Adapted from Choy 2004.

In rheumatoid arthritis (RA), multiple cytokines, including IL-6, TNF-α, IL-1, and IL-17, trigger pro-inflammatory responses through membrane-bound receptors1,7,20-22

  • Receptors for tumor necrosis factor-α (TNF-α) or IL-1 are also expressed as membrane-bound and soluble forms20,21

  • Inflammatory signaling for TNF-α and IL-1 is mediated by the membrane-bound form of the receptor20,21

Cytokine signaling pathways in RA1-7,23

References: 1. Rose-John S, Scheller J, Elson G, Jones SA. Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J Leukoc Biol. 2006;80(2):227-236. 2. Hermanns HM, Müller-Newen G, Heinrich PC, Haan S. Bow to your partner for signaling. Nat Struct Mol Biol. 2005;12(6):476-478. 3. Boulanger MJ, Chow DC, Brevnova EE, Garcia KC. Hexameric structure and assembly of interleukin-6/IL-6 alpha-receptor/gp130 complex. Science. 2003;300(5628):2101-2104. 4. Skiniotis G, Boulanger MJ, Garcia KC, Walz T. Signaling conformations of the tall cytokine receptor gp130 when in complex with IL-6 and IL-6 receptor. Nat Struct Mol Biol. 2005;12(6):545-551. 5. Jones SA, Scheller J, Rose-John S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest. 2011;121(9):3375-3383. 6. Mihara M, Hashizume M, Yoshida H, Suzuki M, Shiina M. IL-6/IL-6 receptor system and its role in physiological and pathological conditions. Clin Sci (Lond). 2012;122(4):143-159. 7. Dayer JM, Choy E. Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor. Rheumatology (Oxford). 2010;49(1):15-24. 8. Mihara M, Moriya Y, Kishimoto T, Ohsugi Y. Interleukin-6 (IL-6) induces the proliferation of synovial fibroblastic cells in the presence of soluble IL-6 receptor. Br J Rheumatol. 1995;34(4):321-325. 9. McInnes IB. Cytokines. In: Firestein GS, Budd RC, Gabriel SE, McInnes IB, O’Dell JR, eds. Kelley’s Textbook of Rheumatology. Vol 1. 9th ed. Philadelphia, PA: Elsevier/Saunders; 2013: 369-381. 10. McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7(6):429-442. 11. Choy EH, Kavanaugh AF, Jones SA. The problem of choice: current biologic agents and future prospects in RA. Nat Rev Rheumatol. 2013;9(3):154-163. 12. Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH, eds. Rheumatology. 5th ed. Philadelphia, PA: MOSBY Elsevier Ltd; 2011. 13. Janeway CJ, Travers P, Walport M, Shlomchik M. Immunobiology: The Immune System in Health and Disease. 5th ed. New York: Garland Science; 2001. 14. Saxena A, Cronstein BN. Acute phase reactants and the concept of inflammation. In: Firestein GS, Budd RC, Gabriel SE, McInnes IB, O’Dell JR, eds. Kelley’s Textbook of Rheumatology. Vol 1. 9th ed. Philadelphia, PA: Elsevier/Saunders. 2013: 818-829. 15. Ito A, Itoh Y, Sasaguri Y, Morimatsu M, Mori Y. Effects of interleukin-6 on the metabolism of connective tissue components in rheumatoid synovial fibroblasts. Arthritis Rheum. 1992;35(10):1197-1201. 16. Okada A, Yamasaki S, Koga T, et al. Adipogenesis of the mesenchymal stromal cells and bone oedema in rheumatoid arthritis. Clin Exp Rheumatol. 2012;30(3):332-337. 17. Ellingsgaard H, Ehses JA, Hammar EB, et al. Interleukin-6 regulates pancreatic alpha-cell mass expansion. Proc Natl Acad Sci U S A. 2008;105(35):13163-13168. 18. Schmitt RM, Bruyns E, Snodgrass HR. Hematopoietic development of embryonic stem cells in vitro: cytokine and receptor gene expression. Genes Dev. 1991;5(5):728-740. 19. Choy E. Clinical experience with inhibition of interleukin-6. Rheum Dis Clin North Am. 2004;30(2):405-415. 20. Colmegna I, Ohata BR, Menard HA. Current understanding of rheumatoid arthritis therapy. Clin Pharmacol Ther. 2012;91(4):607-620. 21. Sha Y, Markovic-Plese S. A role of IL-1R1 signaling in the differentiation of Th17 cells and the development of autoimmune diseases. Self Nonself. 2011;2(1):35-42. 22. Gaffen SL. Structure and signaling in the IL-17 receptor family. Nat Rev Immunol. 2009;9:556-567. 23. Hagihara K, Kagawa S, Kishida Y, Arimitsu J. Anti-cytokine therapy for AA amyloidosis. In: Feng D, ed. Amyloidosis. InTech; June 12, 2013:131-152. Accessed May 15, 2015.