Details

Autor(en) / Beteiligte

• Yan, Isabell
• Schwarz, Jeanette
• Lücke, Karsten
• Schumacher, Neele
• Schumacher, Valéa
• Schmidt, Stefanie
• Rabe, Björn
• Saftig, Paul
• Donners, Marjo
• Rose‐John, Stefan
• Mittrücker, Hans‐Willi
• Chalaris, Athena

Titel

ADAM17 controls IL‐6 signaling by cleavage of the murine IL‐6Rα from the cell surface of leukocytes during inflammatory responses

Ist Teil von

• Journal of leukocyte biology, 2016-05, Vol.99 (5), p.749-760

Ort / Verlag

United States

Erscheinungsjahr

2016

Link zum Volltext

Quelle

Wiley Online Library Journals Frontfile Complete

Beschreibungen/Notizen

• ADAM17 balances IL‐6 signaling by shedding of the murine IL‐6Rα during infection and inflammation. 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.