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.
Costantino
Giuseppina
G
Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
Egerbacher
Monika
M
Kolbe
Thomas
T
Karaghiosoff
Marina
M
Strobl
Birgit
B
Vogl
Claus
C
Helmreich
Magdalena
M
Müller
Mathias
M
D000818:Animals; D004847:Epithelial Cells / Q000378:metabolism; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000473:pathology; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D053634:TYK2 Kinase / Q000235:genetics / Q000378:metabolism*
D019007:P-Selectin; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D053634:TYK2 Kinase; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053511:Matrix Metalloproteinase 14