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

Autor(en)
Eva Hainzl , Silvia Stockinger , Isabella Rauch , Susanne Heider , David Berry , Caroline Lassnig , Clarissa Schwab , Felix Rosebrock , Gabriel Milinovich , Michaela Schlederer , Michael Wagner , Christa Schleper , Alexander Loy , Tim Urich , Lukas Kenner , Xiaonan Han , Thomas Decker , Birgit Strobl , Mathias Müller
Abstrakt

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.

Organisation(en)
Department für Mikrobiologie, Immunbiologie und Genetik , Department für Mikrobiologie und Ökosystemforschung , Forschungsverbund Chemistry Meets Microbiology , Großgeräteeinrichtung für Isotopenforschung , Department für Ökogenomik und Systembiologie
Journal
Journal of Immunology
Band
195
Seiten
5011-24
Anzahl der Seiten
14
ISSN
0022-1767
DOI
https://doi.org/10.4049/jimmunol.1402565
Publikationsdatum
11-2015
Publikationsstatus
Veröffentlicht
Peer-reviewed
Ja
ÖFOS 2012
106022 Mikrobiologie
Link zum Portal
https://ucris.univie.ac.at/portal/de/publications/intestinal-epithelial-cell-tyrosine-kinase-2-transduces-il22-signals-to-protect-from-acute-colitis(dc2af80f-d3f6-4b7e-9085-3efc05df7319).html