Proteolytic Cleavage Governs Interleukin-11 Trans-signaling.

Authors:
Juliane Lokau, Rebecca Nitz, Maria Agthe, Niloufar Monhasery, Samadhi Aparicio-Siegmund, Neele Schumacher, Janina Wolf, Katja Möller-Hackbarth, Georg H Waetzig, Joachim Grötzinger, Gerhard Müller-Newen, Stefan Rose-John, Jürgen Scheller, Christoph Garbers
Year of publication:
2016
Volume:
14
Issue:
7
Issn:
2211-1247
Journal title abbreviated:
CELL REP
Journal title long:
Cell reports
Impact factor:
8.109
Abstract:
Interleukin (IL)-11 has been shown to be a crucial factor for intestinal tumorigenesis, lung carcinomas, and asthma. IL-11 is thought to exclusively mediate its biological functions through cell-type-specific expression of the membrane-bound IL-11 receptor (IL-11R). Here, we show that the metalloprotease ADAM10, but not ADAM17, can release the IL-11R ectodomain. Chimeric proteins of the IL-11R and the IL-6 receptor (IL-6R) revealed that a small juxtamembrane portion is responsible for this substrate specificity of ADAM17. Furthermore, we show that the serine proteases neutrophil elastase and proteinase 3 can also cleave the IL-11R. The resulting soluble IL-11R (sIL-11R) is biologically active and binds IL-11 to activate cells. This IL-11 trans-signaling pathway can be inhibited specifically by the anti-inflammatory therapeutic compound sgp130Fc. In conclusion, proteolysis of the IL-11R represents a molecular switch that controls the IL-11 trans-signaling pathway and widens the number of cells that can be activated by IL-11.