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

Externe Organisation(en)

Veterinärmedizinische Universität Wien, Ludwig Boltzmann Institut für Krebsforschung, Medizinische Universität Wien, Cincinnati Children's Hospital Medical Center

Journal

Journal of Immunology

Band

195

Seiten

5011-5024

Anzahl der Seiten

14

ISSN

0022-1767

DOI

https://doi.org/10.4049/jimmunol.1402565

Publikationsdatum

11-2015

Peer-reviewed

Ja

ÖFOS 2012

106022 Mikrobiologie

ASJC Scopus Sachgebiete

Immunology and Allergy, Immunology

Link zum Portal

https://ucrisportal.univie.ac.at/de/publications/dc2af80f-d3f6-4b7e-9085-3efc05df7319