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Review
. 2011 Sep;121(9):3375-83.
doi: 10.1172/JCI57158. Epub 2011 Sep 1.

Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling

Simon A Jones  1 , Jürgen Scheller, Stefan Rose-John
Affiliations
Review

Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling

Simon A Jones et al. J Clin Invest. 2011 Sep.

Abstract

The successful treatment of certain autoimmune conditions with the humanized anti-IL-6 receptor (IL-6R) antibody tocilizumab has emphasized the clinical importance of cytokines that signal through the β-receptor subunit glycoprotein 130 (gp130). In this Review, we explore how gp130 signaling controls disease progression and examine why IL-6 has a special role among these cytokines as an inflammatory regulator. Attention will be given to the role of the soluble IL-6R, and we will provide a perspective into the clinical blockade of IL-6 activity in autoimmunity, inflammation, and cancer.

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Figures

Figure 1
Figure 1. Receptor composition for cytokines signaling via the β-receptor subunit gp130.
gp130-related cytokines (IL-6, IL-11, IL-27, CNTF, CLC, CT-1, LIF, OSM) bind membrane-bound receptor complexes, which all contain the receptor subunit gp130. These cytokines have diverse functions, not limited to but including the induction of acute phase response protein expression; lymphocyte activation; cytoprotective actions on cardiomyocytes, neuronal cells, and hepatocytes; bone metabolism; hematopoiesis; and liver development and regeneration. IL-6 trans-signaling through the IL-6/sIL-6R complex can fulfill functions of other gp130 cytokines, including blockade of embryonic stem cell differentiation. In addition, since gp130 is expressed in all cells of the body, the IL-6/sIL-6R complex can stimulate cells in additional tissues, which do not express IL-6R, LIF receptor (LIFR), OSMR, IL-11R, CNTF receptor (CNTFR), or the IL-27 receptor subunit WSX-1.
Figure 2
Figure 2. Modes of therapeutic IL-6 blockade.
IL-6–neutralizing antibodies (violet; Table 1) block both classical and trans-signaling of IL-6 by interfering with binding of IL-6 to IL-6R. This might lead to high-level accumulation of IL-6 due to decreased clearance. IL-6R–neutralizing antibodies interfere with binding of IL-6R to IL-6 (green; Table 1) and also block both classical and trans-signaling of IL-6 but only lead to moderate elevation of IL-6 levels due to impaired internalization and subsequent degradation of IL-6. The sgp130Fc protein (red/brown; Table 1) specifically blocks IL-6 trans-signaling without affecting classical signaling via the membrane-bound IL-6R, since IL-6 alone has no measurable affinity to sgp130Fc.
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References

    1. Feldmann M. Development of anti-TNF therapy for rheumatoid arthritis. Nat Rev Immunol. 2002;2(5):364–371. - PubMed
    1. McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7(6):429–442. doi: 10.1038/nri2094. - DOI - PubMed
    1. Ivashkiv LB, Hu X. The JAK/STAT pathway in rheumatoid arthritis: pathogenic or protective? Arthritis Rheum. 2003;48(8):2092–2096. doi: 10.1002/art.11095. - DOI - PubMed
    1. Grivennikov SI, Karin M. Dangerous laison: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev. 2010;21(1):11–19. doi: 10.1016/j.cytogfr.2009.11.005. - DOI - PMC - PubMed
    1. Kishimoto T. IL-6: from its discovery to clinical applications. Int Immunol. 2010;22(5):347–352. doi: 10.1093/intimm/dxq030. - DOI - PubMed

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