TY - JOUR
T1 - Intestinal epithelial cell tyrosine kinase 2 transduces IL-22 signals to protect from acute colitis
AU - Hainzl, Eva
AU - Stockinger, Silvia
AU - Rauch, Isabella
AU - Heider, Susanne
AU - Berry, David
AU - Lassnig, Caroline
AU - Schwab, Clarissa
AU - Rosebrock, Felix
AU - Milinovich, Gabriel
AU - Schlederer, Michaela
AU - Wagner, Michael
AU - Schleper, Christa
AU - Loy, Alexander
AU - Urich, Tim
AU - Kenner, Lukas
AU - Han, Xiaonan
AU - Decker, Thomas
AU - Strobl, Birgit
AU - Müller, Mathias
N1 - Publisher Copyright:
Copyright © 2015 by The American Association of Immunologists, Inc.
PY - 2015/11/15
Y1 - 2015/11/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84958631189&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84958631189&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1402565
DO - 10.4049/jimmunol.1402565
M3 - Article
C2 - 26432894
AN - SCOPUS:84958631189
SN - 0022-1767
VL - 195
SP - 5011
EP - 5024
JO - Journal of Immunology
JF - Journal of Immunology
IS - 10
ER -