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

Speakers received an honorarium from Sanofi Genzyme in connection with these presentations. This content was jointly developed by speakers and Sanofi Genzyme.

 

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

Exploring Dual Signaling & Widespread Biologic Effects of IL-6

In this video, we will discuss the unique dual-signaling mechanism of interleukin-6, or IL-6, which enables it to affect many cell types and cause chronic inflammation and the clinical manifestations of rheumatoid arthritis, or RA.

Unlike most cytokines, the dual-signaling mechanism of IL-6 includes cis-signaling and trans-signaling.

Cis-, or classical signaling, utilizes membrane-bound receptors that are present on a limited number of cells, including hepatocytes and leukocytes (for example, neutrophils, monocytes, macrophages, and some lymphocytes). Cis-signaling is important for anti-inflammatory, homeostatic, and protective functions.

Trans-signaling uses a soluble IL-6 receptor to interact with many additional cells that do not have membrane-bound receptors, such as osteoclasts, fibroblast-like synoviocytes, endothelial cells, adipocytes, and neural cells. This is the predominant IL-6 signaling mechanism observed in inflammatory disease states such as RA.

A key piece of IL-6 signaling- both cis and trans – is the ubiquitously expressed signal-transducing gp130. It is important to note that gp130 is used in the signaling of many other groups of cytokines, such as IL-11 and IL-27.

The complex of IL-6 and its receptor must engage gp130. Alone, IL-6 binding to its receptors will not adequately initiate signaling. When the membrane-bound or the soluble IL-6 receptor/IL-6 complex binds to gp130, homodimerization is induced. This conformational change activates a pair of JAK proteins, which then phosphorylate each other through a process referred to as autophosphorylation. Then they phosphorylate the cytoplasmic tail of the gp130 receptor and initiate downstream signaling.

There are three distinct downstream signaling pathways of IL-6: The JAK/STAT pathway, MAP-kinase pathway, and PI3-kinase pathway. All 3 pathways are critical to IL-6 intracellular signaling in RA that ultimately mediates downstream effects indicative of RA.

The dual signaling of IL-6 allows it to affect almost every cell type, organ, and tissue. Elevated IL-6 levels affect: Hepatocytes, which can contribute to the acute-phase response, restrict the supply of iron to hemoglobin synthesis, and cause metabolic dysregulation. Osteoclasts and fibroblast-like synoviocytes, which leads to bone resorption. Neural and glial cells, which leads to fatigue, pain, altered sleep, morning stiffness, and affects mood. Endothelial cells, which leads to cardiovascular effects. Adipocytes, which leads to metabolic dysregulation.

In summary, cis- and trans-signaling of IL-6 explains its pleiotropic nature; that is, its ability to affect almost all cell types, organs, and tissues.

To find out more about IL-6, please browse additional videos in this series on RAandIL6.com. This video was brought to you by Sanofi Genzyme and Regeneron Pharmaceuticals.

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.