Format

Send to

Choose Destination
J Leukoc Biol. 2016 May;99(5):749-60. doi: 10.1189/jlb.3A0515-207R. Epub 2015 Nov 11.

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

Author information

1
Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
2
Institute for Biochemistry, Medical Faculty, Christian Albrechts University, Kiel, Germany; and.
3
Department of Pathology, Maastricht University, Maastricht, The Netherlands.
4
Institute for Biochemistry, Medical Faculty, Christian Albrechts University, Kiel, Germany; and achalaris@biochem.uni-kiel.de.

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.

KEYWORDS:

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

PMID:
26561568
DOI:
10.1189/jlb.3A0515-207R
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center