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

Autoren:Hainzl, Eva (Veterinärmedizinische Universität Wien); Stockinger, Silvia (Veterinärmedizinische Universität Wien); Rauch, Isabella; Heider, Susanne (Ludwig Boltzmann Institut für Krebsforschung); Berry, David; Lassnig, Caroline (Veterinärmedizinische Universität Wien); Schwab, Clarissa; Rosebrock, Felix; Milinovich, Gabriel; Schlederer, Michaela (Ludwig Boltzmann Institut für Krebsforschung); Wagner, Michael; Schleper, Christa; Loy, Alexander; Urich, Tim; Kenner, Lukas (Medizinische Universität Wien); Han, Xiaonan (Cincinnati Children's Hospital Medical Center); Decker, Thomas; Strobl, Birgit (Veterinärmedizinische Universität Wien); Müller, Mathias (Veterinärmedizinische Universität Wien)

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.

Anzahl der Seiten:14
Journaltitel:Journal of Immunology
Peer reviewed:true
Digital Object Identifier (DOI):
Bibliographische Notiz:Copyright © 2015 by The American Association of Immunologists, Inc.