title: Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis.
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.
authors.affiliation: Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, 1210 Vienna, Austria;
authors.forename: Eva
authors.initials: E
authors.lastname: Hainzl
authors.affiliation: Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, 1210 Vienna, Austria; mathias.mueller@vetmeduni.ac.at silvia.stockinger@vetmeduni.ac.at.
authors.forename: Silvia
authors.initials: S
authors.lastname: Stockinger
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720;
authors.forename: Isabella
authors.initials: I
authors.lastname: Rauch
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, 1090 Vienna, Austria;
authors.forename: Susanne
authors.initials: S
authors.lastname: Heider
authors.affiliation: Department of Microbiology and Ecosystem Science, University of Vienna, 1090 Vienna, Austria;
authors.forename: David
authors.initials: D
authors.lastname: Berry
authors.affiliation: Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, 1210 Vienna, Austria; Biomodels Austria, University of Veterinary Medicine, Vienna, 1210 Vienna, Austria;
authors.forename: Caroline
authors.initials: C
authors.lastname: Lassnig
authors.affiliation: Department of Ecogenomics and Systems Biology, University of Vienna, 1090 Vienna, Austria;
authors.forename: Clarissa
authors.initials: C
authors.lastname: Schwab
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria;
authors.forename: Felix
authors.initials: F
authors.lastname: Rosebrock
authors.affiliation: Department of Ecogenomics and Systems Biology, University of Vienna, 1090 Vienna, Austria;
authors.forename: Gabriel
authors.initials: G
authors.lastname: Milinovich
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, 1090 Vienna, Austria;
authors.forename: Michaela
authors.initials: M
authors.lastname: Schlederer
authors.affiliation: Department of Microbiology and Ecosystem Science, University of Vienna, 1090 Vienna, Austria;
authors.forename: Michael
authors.initials: M
authors.lastname: Wagner
authors.affiliation: Department of Ecogenomics and Systems Biology, University of Vienna, 1090 Vienna, Austria;
authors.forename: Christa
authors.initials: C
authors.lastname: Schleper
authors.affiliation: Department of Microbiology and Ecosystem Science, University of Vienna, 1090 Vienna, Austria;
authors.forename: Alexander
authors.initials: A
authors.lastname: Loy
authors.affiliation: Department of Ecogenomics and Systems Biology, University of Vienna, 1090 Vienna, Austria;
authors.forename: Tim
authors.initials: T
authors.lastname: Urich
authors.affiliation: 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.
authors.forename: Lukas
authors.initials: L
authors.lastname: Kenner
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Han
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria;
authors.forename: Thomas
authors.initials: T
authors.lastname: Decker
authors.affiliation: Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, 1210 Vienna, Austria;
authors.forename: Birgit
authors.initials: B
authors.lastname: Strobl
authors.affiliation: 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.
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
mesh_terms: D000818:Animals; D044082:Citrobacter rodentium / Q000276:immunology; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004756:Enterobacteriaceae Infections / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology; D007589:Job Syndrome / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D053634:TYK2 Kinase / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D000097043:Interleukin-22
chemical_list: D007378:Interleukins; D050796:STAT3 Transcription Factor; D053634:TYK2 Kinase; D000097043:Interleukin-22; C494087:Stat3 protein, mouse; C499356:Tyk2 protein, mouse