title: Apoptosis is a natural stimulus of IL6R shedding and contributes to the proinflammatory trans-signaling function of neutrophils.
abstract: Interleukin 6 (IL6) trans-signaling has emerged as a prominent regulator of immune responses during both innate and acquired immunity. Regulation of IL6 trans-signaling is reliant upon the release of soluble IL6 receptor (sIL6R), which binds IL6 to create an agonistic IL6/sIL6R complex capable of activating cell types that would not normally respond to IL6 itself. Here we show that intrinsic and extrinsic apoptotic stimulation by DNA damage, cytokine deprivation, and Fas stimulation promotes shedding of sIL6R. Apoptosis-induced shedding of the IL6R was caspase dependent but PKC independent, with inhibition of ADAM17 preventing IL6R shedding. Such insight is relevant to the control of acute inflammation, where transition from the initial neutrophil infiltration to a more sustained population of mononuclear cells is essential for the resolution of the inflammatory process. This transitional event is governed by IL6 trans-signaling. This study demonstrates that IL6R is shed from apoptotic human neutrophils. In vivo studies in a murine inflammation model showed that neutrophil depletion resulted in reduced local sIL6R levels and a concomitant decrease in mononuclear cells, suggesting that apoptosis-induced IL6R shedding from neutrophils promotes IL6 trans-signaling and regulates the attraction of monocytic cells involved in the clearance of apoptotic neutrophils.
authors.affiliation: Department of Biochemistry, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Athena
authors.initials: A
authors.lastname: Chalaris
authors.forename: Björn
authors.initials: B
authors.lastname: Rabe
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Paliga
authors.forename: Hans
authors.initials: H
authors.lastname: Lange
authors.forename: Tamas
authors.initials: T
authors.lastname: Laskay
authors.forename: Ceri A
authors.initials: CA
authors.lastname: Fielding
authors.forename: Simon A
authors.initials: SA
authors.lastname: Jones
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D053222:Fas Ligand Protein / Q000378:metabolism; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D007249:Inflammation / Q000276:immunology / Q000503:physiopathology*; D015850:Interleukin-6 / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D019014:fas Receptor / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; D019014:fas Receptor; D011493:Protein Kinase C; D020169:Caspases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse