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J Immunol. 2015 Nov 15;195(10):5011-24. doi: 10.4049/jimmunol.1402565. Epub 2015 Oct 2.

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

Author information

1
Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, 1210 Vienna, Austria;
2
Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, 1210 Vienna, Austria; mathias.mueller@vetmeduni.ac.at silvia.stockinger@vetmeduni.ac.at.
3
Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720;
4
Ludwig Boltzmann Institute for Cancer Research, 1090 Vienna, Austria;
5
Department of Microbiology and Ecosystem Science, University of Vienna, 1090 Vienna, Austria;
6
Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, 1210 Vienna, Austria; Biomodels Austria, University of Veterinary Medicine, Vienna, 1210 Vienna, Austria;
7
Department of Ecogenomics and Systems Biology, University of Vienna, 1090 Vienna, Austria;
8
Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria;
9
Ludwig Boltzmann Institute for Cancer Research, 1090 Vienna, Austria; Institute for Clinical Pathology, Medical University Vienna, 1090 Vienna, Austria; Unit of Pathology of Laboratory Animals, University of Veterinary Medicine, Vienna, 1210 Vienna, Austria; and.
10
Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
11
Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, 1210 Vienna, Austria; Biomodels Austria, University of Veterinary Medicine, Vienna, 1210 Vienna, Austria; mathias.mueller@vetmeduni.ac.at silvia.stockinger@vetmeduni.ac.at.

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.

PMID:
26432894
PMCID:
PMC4635564
DOI:
10.4049/jimmunol.1402565
[Indexed for MEDLINE]
Free PMC Article

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