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IL-6 binds either to the membrane-bound IL-6 receptor-\u03b1 (classic signaling) or to the soluble IL-6 receptor-\u03b1 (trans-signaling) to initiate signal transduction via gp130 activation. Because classic and trans-signaling of IL-6 fulfill different tasks during immune responses, controlled shedding of the membrane-bound IL-6 receptor-\u03b1 from the surface of immune cells can be considered a central regulator of IL-6 function. The results from cell culture-based experiments have implicated both a disintegrin and metalloprotease 10 and a disintegrin and metalloprotease 17 in IL-6 receptor-\u03b1 shedding. However, the nature of the protease mediating IL-6 receptor-\u03b1 release in vivo is not yet known. We used hypomorphic a disintegrin and metalloprotease 17 mice and conditional a disintegrin and metalloprotease 10 knock-out mice to identify the natural protease of the murine IL-6 receptor-\u03b1. Circulating homeostatic soluble IL-6 receptor-\u03b1 levels are not dependent on a disintegrin and metalloprotease 10 or 17 activity. However, during Listeria monocytogenes infection, IL-6 receptor-\u03b1 cleavage by the \u03b1-secretase a disintegrin and metalloprotease 17 is rapidly induced from the surface of different leukocyte populations. In contrast, CD4-Cre-driven a disintegrin and metalloprotease 10 deletion in T cells did not influence IL-6 receptor-\u03b1 shedding from these cells after L. monocytogenes infection. A disintegrin and metalloprotease 17 was also required for IL-6 receptor-\u03b1 ectodomain cleavage and release during endotoxemia. These results demonstrate a novel physiologic role for a disintegrin and metalloprotease 17 in regulating murine IL-6 signals during inflammatory processes.<\/jats:p>","DOI":"10.1189\/jlb.3a0515-207r","type":"journal-article","created":{"date-parts":[[2015,11,12]],"date-time":"2015-11-12T02:49:35Z","timestamp":1447296575000},"page":"749-760","source":"Crossref","is-referenced-by-count":59,"title":["ADAM17 controls IL-6 signaling by cleavage of the murine IL-6R\u03b1 from the cell surface of leukocytes during inflammatory responses"],"prefix":"10.1093","volume":"99","author":[{"given":"Isabell","family":"Yan","sequence":"first","affiliation":[{"name":"Institute of Immunology, University Medical Center Hamburg-Eppendorf , Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanette","family":"Schwarz","sequence":"additional","affiliation":[{"name":"Institute for Biochemistry, Medical Faculty, Christian Albrechts University , Kiel , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karsten","family":"L\u00fccke","sequence":"additional","affiliation":[{"name":"Institute of Immunology, University Medical Center Hamburg-Eppendorf , Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neele","family":"Schumacher","sequence":"additional","affiliation":[{"name":"Institute for Biochemistry, Medical Faculty, Christian Albrechts University , Kiel , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9a","family":"Schumacher","sequence":"additional","affiliation":[{"name":"Institute of Immunology, University Medical Center Hamburg-Eppendorf , Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Institute for Biochemistry, Medical Faculty, Christian Albrechts University , Kiel , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"Rabe","sequence":"additional","affiliation":[{"name":"Institute for Biochemistry, Medical Faculty, Christian Albrechts University , Kiel , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Saftig","sequence":"additional","affiliation":[{"name":"Institute for Biochemistry, Medical Faculty, Christian Albrechts University , Kiel , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjo","family":"Donners","sequence":"additional","affiliation":[{"name":"Department of Pathology, Maastricht University , Maastricht , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Rose-John","sequence":"additional","affiliation":[{"name":"Institute for Biochemistry, Medical Faculty, Christian Albrechts University , Kiel , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans-Willi","family":"Mittr\u00fccker","sequence":"additional","affiliation":[{"name":"Institute of Immunology, University Medical Center Hamburg-Eppendorf , Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athena","family":"Chalaris","sequence":"additional","affiliation":[{"name":"Institute for Biochemistry, Medical Faculty, Christian Albrechts University , Kiel , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,11,11]]},"reference":[{"key":"2023013012482643000_B1","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1038\/nri3499","article-title":"Metalloproteinases and their natural inhibitors in inflammation and immunity","volume":"13","author":"Khokha","year":"2013","journal-title":"Nat. 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