Dual
Signaling

The unique dual signaling of IL-6 allows for
diverse biological effects throughout the body1-6

Unlike most cytokines, IL-6 is able to signal via both membrane-bound receptors (cis-signaling) and soluble receptors (trans-signaling), which causes it to exert a broad range of biological activity, contributing to chronic inflammation and clinical manifestations.1-6 The ability of IL-6 to signal via both membrane-bound and soluble receptors explains its pleiotropic effects.3,5,6

IL-6 signals through
cis-signaling and
trans-signaling1,2

Cis-signaling
(membrane-bound
receptors)
  • Cis-signaling primarily mediates the homeostatic and protective activities of IL-6, and is thus the predominant signaling mechanism of IL-6 in healthy individuals2,4,5
  • Cis-signaling requires IL-6 binding to its membrane-bound receptor (mIL-6R), and is therefore limited to cells that express mIL-6R, including hepatocytes, neutrophils, monocytes, macrophages, and some lymphocytes7
Trans-signaling
(soluble receptors)
  • Trans-signaling promotes cellular changes that drive chronic inflammation and disease development2,4,5
  • Trans-signaling allows IL-6 to interact with cells that do not express mIL-6R, including osteoclasts, synoviocytes, endothelial cells, and neural cells3,7,8
LISTEN NOW:
Dual signaling: the driver behind the pleiotropic nature of IL-6
by Dr Alan Epstein
 

The interaction of IL-6 with ubiquitously expressed gp130 in both cis- and trans-signaling allows it to act directly on almost all cell types3,6,7

In cis-signaling, IL-6 binds with its membrane bound IL-6 receptor (mIL-6R). In trans-signaling, a soluble IL-6 receptor (sIL-6R) binds IL-6 and membrane-bound glycoprotein 130 (gp130).

IL-6 binds with its membrane-bound IL-6 receptor (mIL-6R)

In cis-signaling, IL-6 binds with its membrane bound IL-6 receptor (mIL-6R). In trans-signaling, a soluble IL-6 receptor (sIL-6R) binds IL-6 and membrane-bound glycoprotein 130 (gp130).

A soluble IL-6 receptor (sIL-6R) binds IL-6 and membrane-bound glycoprotein 130 (gp130)

Major sources of IL-6 include monocytes/macrophages, endothelial cells, and synovial fibroblasts. The major cell targets of IL-6 include synovial fibroblasts, T cell, neutrophil, hepatocytes, osteoclast, maturation of megakaryocytes, and B cell which then targets hyper-γ-globulinemia, autoantibodies, and thrombocytosis. Major sources of IL-6 include monocytes/macrophages, endothelial cells, and synovial fibroblasts. The major cell targets of IL-6 include synovial fibroblasts, T cell, neutrophil, hepatocytes, osteoclast, maturation of megakaryocytes, and B cell which then targets hyper-γ-globulinemia, autoantibodies, and thrombocytosis.

Adapted from Choy, 2004.9

References: 1. Choy E. Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology (Oxford). 2012;51(suppl 5):v3-v11. doi:10.1093/rheumatology/kes113. 2. Calabrese LH, Rose-John S. IL-6 biology: implications for clinical targeting in rheumatic disease. Nat Rev Rheumatol. 2014;10(12):720-727. Published correction appears in Nat Rev Rheumatol. 2014;10(12):i. 3. Choy EHS, Calabrese LH. Neuroendocrine and neurophysiological effects of interleukin 6 in rheumatoid arthritis. Rheumatology (Oxford). 2018;57(11):1885-1895. 4. Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015;16:448-457. 5. Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta. 2011;1813(5):878-888. 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. Adam N, Rabe B, Suthaus J, Grötzinger J, Rose-John S, Scheller J. Unraveling viral interleukin-6 binding to gp130 and activation of STAT-signaling pathways independently of the interleukin-6 receptor. J Virol. 2009;83(10):5117-5126. 9. Choy E. Clinical experience with inhibition of interleukin-6. Rheum Dis Clin North Am. 2004;30(2):405-415.