title: ADAM17 controls IL-6 signaling by cleavage of the murine IL-6Rα from the cell surface of leukocytes during inflammatory responses.
abstract: The cytokine IL-6 is part of a regulatory signaling network that controls immune responses. IL-6 binds either to the membrane-bound IL-6 receptor-α (classic signaling) or to the soluble IL-6 receptor-α (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-α 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-α shedding. However, the nature of the protease mediating IL-6 receptor-α 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-α. Circulating homeostatic soluble IL-6 receptor-α levels are not dependent on a disintegrin and metalloprotease 10 or 17 activity. However, during Listeria monocytogenes infection, IL-6 receptor-α cleavage by the α-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-α shedding from these cells after L. monocytogenes infection. A disintegrin and metalloprotease 17 was also required for IL-6 receptor-α 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.
authors.affiliation: Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Isabell
authors.initials: I
authors.lastname: Yan
authors.affiliation: Institute for Biochemistry, Medical Faculty, Christian Albrechts University, Kiel, Germany; and.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Schwarz
authors.affiliation: Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Karsten
authors.initials: K
authors.lastname: Lücke
authors.affiliation: Institute for Biochemistry, Medical Faculty, Christian Albrechts University, Kiel, Germany; and.
authors.forename: Neele
authors.initials: N
authors.lastname: Schumacher
authors.affiliation: Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Valéa
authors.initials: V
authors.lastname: Schumacher
authors.affiliation: Institute for Biochemistry, Medical Faculty, Christian Albrechts University, Kiel, Germany; and.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Institute for Biochemistry, Medical Faculty, Christian Albrechts University, Kiel, Germany; and.
authors.forename: Björn
authors.initials: B
authors.lastname: Rabe
authors.affiliation: Institute for Biochemistry, Medical Faculty, Christian Albrechts University, Kiel, Germany; and.
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.affiliation: Department of Pathology, Maastricht University, Maastricht, The Netherlands.
authors.forename: Marjo
authors.initials: M
authors.lastname: Donners
authors.affiliation: Institute for Biochemistry, Medical Faculty, Christian Albrechts University, Kiel, Germany; and.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Hans-Willi
authors.initials: HW
authors.lastname: Mittrücker
authors.affiliation: Institute for Biochemistry, Medical Faculty, Christian Albrechts University, Kiel, Germany; and achalaris@biochem.uni-kiel.de.
authors.forename: Athena
authors.initials: A
authors.lastname: Chalaris
mesh_terms: D000072197:ADAM10 Protein / Q000378:metabolism; D000072198:ADAM17 Protein / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D019446:Endotoxemia / Q000276:immunology / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D007249:Inflammation / Q000097:blood / Q000378:metabolism* / Q000473:pathology*; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism*; D008089:Listeria monocytogenes / Q000502:physiology; D008088:Listeriosis / Q000097:blood / Q000276:immunology / Q000473:pathology; D008810:Mice, Inbred C57BL; D019947:Receptors, Interleukin-6 / Q000097:blood / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein
keywords: Listeria monocytogenes; Metalloproteases; endotoxin shock; shedding; trans-signalling