ADAM17 controls IL-6 signaling by cleavage of the murine IL-6R alpha from the cell surface of leukocytes during inflammatory responses

Isabell Yan, Jeanette Schwarz, Karsten Luecke, Neele Schumacher, Valea Schumacher, Stefanie Schmidt, Bjoern Rabe, Paul Saftig, Marjo Donners, Stefan Rose-John, Hans-Willi Mittruecker, Athena Chalaris*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

44 Citations (Web of Science)


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-alpha (classic signaling) or to the soluble IL-6 receptor-alpha (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-alpha 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-alpha shedding. However, the nature of the protease mediating IL-6 receptor-alpha 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-alpha. Circulating homeostatic soluble IL-6 receptor-alpha levels are not dependent on a disintegrin and metalloprotease 10 or 17 activity. However, during Listeria monocytogenes infection, IL-6 receptor-alpha cleavage by the alpha-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-alpha shedding from these cells after L. monocytogenes infection. A disintegrin and metalloprotease 17 was also required for IL-6 receptor-alpha 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.
Original languageEnglish
Pages (from-to)749-760
JournalJournal of Leukocyte Biology
Issue number5
Publication statusPublished - May 2016


  • Metalloproteases
  • shedding
  • Listeria monocytogenes
  • endotoxin shock
  • trans-signalling

Cite this