Proteolytic Cleavage Governs Interleukin-11 Trans-signaling.
Article Details
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Lokau J, Nitz R, Agthe M, Monhasery N, Aparicio-Siegmund S, Schumacher N, Wolf J, Moller-Hackbarth K, Waetzig GH, Grotzinger J, Muller-Newen G, Rose-John S, Scheller J, Garbers C
Proteolytic Cleavage Governs Interleukin-11 Trans-signaling.
Cell Rep. 2016 Feb 23;14(7):1761-1773. doi: 10.1016/j.celrep.2016.01.053. Epub 2016 Feb 11.
- PubMed ID
- 26876177 [ View in PubMed]
- 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.