ID: 132: Characterization of the limited proteolysis of the interleukin-6 and interleukin-11 receptor by neutrophil serine proteases

The pleiotropic cytokines IL-6 and IL-11 both belong to the IL-6 family of cytokines and can signal through a ubiquitously expressed glycoprotein (gp) 130 β -receptor in combination with a membrane-bound cytokine-specific α -receptor. Formation of the signalling complexes results in the activation of intracellular signalling pathways, mainly the Jak/STAT cascade. It is known that IL-6 can also bind and signal via a soluble receptor (sIL-6R). This so-called trans-signalling is primarily involved in pathophysiology, while classic-signalling through the cell-bound receptor is regarded as regenerative and beneficial. Whereas ADAM proteases are thought to be the main sheddases of the IL-6R, there are no reports about a sheddase involved in the generation of the sIL-11R, and the occurrence of a soluble form of the IL-11R has not been described so far. Here we report that the IL-6R and IL-11R are novel substrates of different neutrophil-derived serine proteases. Our studies showed that these serine proteases cleave the cell-bound receptors in their ectodomain in order to release a functional soluble receptor. Thereby, purified cathepsin G efficiently cleaved membrane-bound IL-6R, whereas treatment with proteinase 3 and neutrophil elastase predominantly resulted in the production of the soluble IL-11R. Further experiments with chimeras of the IL-6R and the IL-11R revealed how the three proteases are able to discriminate between the two substrates.