Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer

Journal of Leukocyte Biology

Greg Elson³  Simon A. Jones¹  Jürgen Scheller²  Stefan Rose-John² 

[1] Department of Medical Biochemistry and Immunology, The School of Medicine Cardiff University, Wales, United Kingdom Department of Medical Biochemistry and Immunology, The School of Medicine Cardiff University, Wales, United Kingdom Department of Medical Biochemistry and Immunology, The School of Medicine Cardiff University, Wales, United KingdomBiochemisches Institut, Christian-Albrechts-Universität zu Kiel, Germany; Biochemisches Institut, Christian-Albrechts-Universität zu Kiel, Germany; Biochemisches Institut, Christian-Albrechts-Universität zu Kiel, Germany;;NovImmune SA, Geneva, Switzerland; and NovImmune SA, Geneva, Switzerland; and NovImmune SA, Geneva, Switzerland; and

关键词: cytokine;    cytokine receptor;    gp130;    sgp130Fc fusion protein;   

DOI  :  10.1189/jlb.1105674

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Cytokine receptors, which exist in membrane-bound and soluble forms, bind their ligands with comparable affinity. Although most soluble receptors are antagonists and compete with their membrane-associated counterparts for the ligands, certain soluble receptors are agonists. In these cases, complexes of ligand and soluble receptor bind on target cells to second receptor subunits and initiate intracellular signaling. The soluble receptors of the interleukin (IL)-6 family of cytokines (sIL-6R, sIL-11R, soluble ciliary neurotrophic factor receptor) are agonists capable of transmitting signals through interaction with the universal signal-transducing receptor for all IL-6 family cytokines, gp130. In vivo, the IL-6/sIL-6R complex stimulates several types of cells, which are unresponsive to IL-6 alone, as they do not express the membrane IL-6R. We have named this process trans-signaling. The generation of soluble cytokine receptors occurs via two distinct mechanismslimited proteolysis and translationfrom differentially spliced mRNA. We have demonstrated that a soluble form of the IL-6 family signaling receptor subunit gp130, which is generated by differential splicing, is the natural inhibitor of IL-6 trans-signaling responses. We have shown that in many chronic inflammatory diseases, including chronic inflammatory bowel disease, peritonitis, rheumatoid arthritis, asthma, as well as colon cancer, IL-6 trans-signaling is critically involved in the maintenance of a disease state, by promoting transition from acute to chronic inflammation. Moreover, in all these models, the course of the disease can be disrupted by specifically interfering with IL-6 trans-signaling using the soluble gp130 protein. The pathophysiological mechanisms by which the IL-6/sIL-6R complex regulates the inflammatory state are discussed.

【 授权许可】

Unknown