Abstract
Background Interleukin-6 type cytokines are mainly involved in inflammation by controlling differentiation, proliferation, migration, and apoptosis of target cells. A dysfunction of the complex regulatory cytokine network might lead to acute and chronic inflammation, autoimmune diseases or neoplastic disorders. IL-6 deficient mice were found to be resistant to collagenand antigen-induced arthritis, highlighting the role of IL-6 in chronic inflammation and autoimmune diseases. The IL-6 receptor complex consists of the signal-transducing gp130 receptor and the non-signaling IL-6 receptor (IL-6R) which exists in membrane bound and soluble forms. A soluble form of the human IL-6R (sIL-6R) is mainly generated by limited proteolysis (ectodomain shedding) but also by alternative splicing. IL-6 signaling via the membrane-bound IL-6R and gp130 is called classic signaling, whereas IL-6 signaling via the soluble IL-6R and gp130 is referred to as IL-6 trans-signaling. Gp130 is ubiquitously expressed, whereas the membrane-bound IL-6R is mainly expressed on lymphocytes and hepatocytes. Therefore, IL-6 trans-signaling virtually expands IL-6 signaling to all cells of the body. Using the specific trans-signaling inhibitor soluble gp130 (sgp130), we showed that IL-6R ectodomain shedding which facilitates IL-6 trans-signaling is the crucial step in the development and the progression of chronic inflammatory disorders and inflammation-induced cancer.
Highlights
Interleukin-6 type cytokines are mainly involved in inflammation by controlling differentiation, proliferation, migration, and apoptosis of target cells
Deletion of 5 additional juxtamembrane located amino acids in the aforementioned delta10 IL-6 receptor (IL-6R) variant abolishes ADAM10-mediated ectodomain shedding of the IL-6R [2], suggesting that the ADAM10 cleavage site is in close proximity to the ADAM17 cleavage site
We showed that only about 20 of the 52 amino acids of the IL-6R stalk region are needed for biological activity of the IL-6R, which supported a model of the IL-6/IL-6R/gp130 signal transducing complex, in which the gp130 receptor chain has a C-shaped structure after IL-6/IL-6R/gp130 complex formation [2]
Summary
Interleukin-6 type cytokines are mainly involved in inflammation by controlling differentiation, proliferation, migration, and apoptosis of target cells. Structural requirements of IL-6R ectodomain shedding Most post-transcriptional modifications such as phosphorylation, which control the fate and activity of proteins, are completely reversible. The generated soluble IL-6R (sIL-6R) itself is biologically active and can mediate IL-6 trans-signaling on cells expressing gp130.
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