Pubmed- Function and proteolytic generation of the soluble interleukin-6 receptor in health and disease - IBD Reporter Newsfeed - IBD Support Group Forums - IBDsupport.org

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Pubmed- Function and proteolytic generation of the soluble interleukin-6 receptor in health and disease


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Posted 10 October 2021 - 07:25 AM

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Biochim Biophys Acta Mol Cell Res. 2021 Oct 6:119143. doi: 10.1016/j.bbamcr.2021.119143. Online ahead of print.

ABSTRACT

The pleiotropic cytokine interleukin-6 (IL-6) is involved in numerous physiological and pathophysiological functions that include development, immune cell differentiation, inflammation and cancer. IL-6 can signal via the membrane-bound IL-6 receptor (IL-6R, classic signaling) or via soluble forms of the IL-6R (sIL-6R, trans-signaling). Both modes of signaling induce the formation of a homodimer of the signal transducing β-receptor glycoprotein 130 (gp130) and the activation of several intracellular signaling cascades, e.g. the Jak/STAT pathway. Intriguingly, only IL-6 trans-signaling is required for the pro-inflammatory properties of IL-6, while regenerative and anti-inflammatory functions are mediated via classic signaling. The sIL-6R is generated by different molecular mechanisms, including alternative mRNA splicing, proteolysis of the membrane-bound IL-6R and the release of extracellular vesicles. In this review, we give an in-depth overview on these molecular mechanisms with a special emphasize on IL-6R cleavage by the metalloprotease ADAM17 and other proteases. We discuss the biological functions of the sIL-6R and highlight attempts to selectively block IL-6 trans-signaling in pre-clinical animal models as well as in clinical studies in patients with inflammatory bowel disease.

PMID:34626681 | DOI:10.1016/j.bbamcr.2021.119143


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