Role of the metalloprotease ADAM10 in Interleukin-11 signaling

• Applicant: Professor Dr. Christoph Garbers
• Subject Area: Immunology ; Biochemistry
• Term: from 2013 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 248403029

The cytokine Interleukin-11 (IL-11) is best known for its anti-inflammatory and regenerative functions, especially in the heart and the colon. Recent data however point to a pro-inflammatory and pro-cancerogenetic role of IL-11 in bone and gastric cancer formation. Until now, only a classic signaling pathway through the membrane-bound IL-11 receptor (IL-11R) has been described. Our recent data show, however, that the membrane-bound IL-11R can be cleaved off by the metalloprotease ADAM10, but not ADAM17, resulting in a soluble IL-11R (sIL-11R). Experiments with chimeric receptors of IL-11R and IL-6R revealed that the so-called stalk region of the IL-11R is responsible for the selectivity of ADAM10 and ADAM17. The sIL-11R is able to bind IL-11, and this complex can activate cells that do not express IL-11R through a trans-signaling pathway. Furthermore, we found for the first time that sIL-11R can be detected in the serum of healthy humans.Aim of this proposal is therefore to determine which inductors activate the limited proteolysis of the IL-11R by ADAM10, and whether there are differences between mice and humans. Furthermore, we will map the exact cleavage site of the IL-11R used by ADAM10 via a proteomics approach and several IL-11R mutants, and investigate if the IL-11R is subsequently cleaved by other proteases, e. g. the gamma-secretase. We will also isolate sIL-11R out of human and murine serum to determine whether it derives from limited proteolysis of the membrane-bound precursor or alternative splicing of the IL-11R mRNA. IL-11 mutants with antagonizing functions as well as inhibitory antibodies will be developed and characterized as tools to inhibit the pro-inflammatory properties of IL-11. Finally, to further investigate IL-11 classic and trans-signaling, a transgenic mouse expressing sIL-11R and an IL-11R reporter mouse will be generated and initially characterized.

• DFG Programme: Research Grants