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Type of publication: Journal Article
Type of document: Full Paper

Year: 2015

Authors: Hainzl, E; Stockinger, S; Rauch, I; Heider, S; Berry, D; Lassnig, C; Schwab, C; Rosebrock, F; Milinovich, G; Schlederer, M; Wagner, M; Schleper, C; Loy, A; Urich, T; Kenner, L; Han, X; Decker, T; Strobl, B; Müller, M

Title: Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis.

Source: J Immunol. 2015; 195(10):5011-5024



Authors Vetmeduni Vienna:

Hainzl Eva
Kenner Lukas
Lassnig Caroline
Müller Mathias
Stockinger Silvia
Strobl Birgit

Vetmed Research Units
Institute of Pathology, Pathology of Laboratory Animals
Institute of Animal Breeding and Genetics, Unit of Molecular Genetics


Project(s): Jak Stat - Signalling from Basis to Disease


Abstract:
In the intestinal tract, IL-22 activates STAT3 to promote intestinal epithelial cell (IEC) homeostasis and tissue healing. The mechanism has remained obscure, but we demonstrate that IL-22 acts via tyrosine kinase 2 (Tyk2), a member of the Jak family. Using a mouse model for colitis, we show that Tyk2 deficiency is associated with an altered composition of the gut microbiota and exacerbates inflammatory bowel disease. Colitic Tyk2(-/-) mice have less p-STAT3 in colon tissue and their IECs proliferate less efficiently. Tyk2-deficient primary IECs show reduced p-STAT3 in response to IL-22 stimulation, and expression of IL-22-STAT3 target genes is reduced in IECs from healthy and colitic Tyk2(-/-) mice. Experiments with conditional Tyk2(-/-) mice reveal that IEC-specific depletion of Tyk2 aggravates colitis. Disease symptoms can be alleviated by administering high doses of rIL-22-Fc, indicating that Tyk2 deficiency can be rescued via the IL-22 receptor complex. The pivotal function of Tyk2 in IL-22-dependent colitis was confirmed in Citrobacter rodentium-induced disease. Thus, Tyk2 protects against acute colitis in part by amplifying inflammation-induced epithelial IL-22 signaling to STAT3.

Keywords Pubmed: Animals
Citrobacter rodentium/immunology
Colitis/genetics
Colitis/immunology*
Colitis/pathology
Enterobacteriaceae Infections/genetics
Enterobacteriaceae Infections/immunology
Enterobacteriaceae Infections/pathology
Interleukins/genetics
Interleukins/immunology*
Intestinal Mucosa/immunology*
Intestinal Mucosa/pathology
Job Syndrome/genetics
Job Syndrome/immunology
Job Syndrome/pathology
Mice
Mice, Knockout
STAT3 Transcription Factor/genetics
STAT3 Transcription Factor/immunology
Signal Transduction/genetics
Signal Transduction/immunology*
TYK2 Kinase/deficiency
TYK2 Kinase/genetics
TYK2 Kinase/immunology*


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