Tyk2 and signal transducer and activator of transcription 1 contribute to intestinal I/R injury.

Previously, we have shown that the Jak-signal transducer and activator of transcription signaling constituents Tyk2 and STAT1 play a role in the development of multiple organ failure during endotoxin shock. Here, we report that Tyk2 and STAT1 contribute to death caused by intestinal I/R injury. Tyk2- and STAT1-deficient mice showed increased survival to I/R because their intestines were protected from gross histomorphological tissue destruction and neutrophil infiltration. On the molecular level, the reduced ischemia induced inflammatory response in mutant versus wild-type mice was accompanied by an impaired up-regulation of the adhesion molecules P-selectin and intercellular adhesion molecule 1 and of the matrix metalloproteinases (MMPs) MMP-2, MMP-9, and MMP-14 in the reperfused intestine. In conclusion, this study demonstrates for the first time that Tyk2 or STAT1 promote intestinal I/R-induced shock based on a deregulated local inflammatory response and a destruction of the gut intestinal barrier.