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

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2015 Oct 4

PMID 26432894

Citations 27

Authors

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 Muller

Affiliations

Soon will be listed here.

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.

Citing Articles

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Saffron reduces the liver fibrosis in mice by inhibiting the JAK/STAT3 pathway.

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Epithelial dysfunction is prevented by IL-22 treatment in a Citrobacter rodentium-induced colitis model that shares similarities with inflammatory bowel disease.

Zhu Q, Korenfeld D, Suarez-Fueyo A, Graham S, Jin L, Punit S Mucosal Immunol. 2022; 15(6):1338-1349.

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Tyk2 is a tumor suppressor in colorectal cancer.

Moritsch S, Modl B, Scharf I, Janker L, Zwolanek D, Timelthaler G Oncoimmunology. 2022; 11(1):2127271.

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References

Lian L, Lau T, Lee V, Lee W, Hilmi I, Goh K . Lack of association between TYK2 and STAT3 genes and Crohn's disease in the Malaysian population. Genet Mol Res. 2013; 12(1):167-74. DOI: 10.4238/2013.January.24.9. View

Zenewicz L, Yancopoulos G, Valenzuela D, Murphy A, Stevens S, Flavell R . Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity. 2008; 29(6):947-57. PMC: 3269819. DOI: 10.1016/j.immuni.2008.11.003. View

Strobl B, Stoiber D, Sexl V, Mueller M . Tyrosine kinase 2 (TYK2) in cytokine signalling and host immunity. Front Biosci (Landmark Ed). 2011; 16(9):3214-32. DOI: 10.2741/3908. View

Strobl B, Bubic I, Bruns U, Steinborn R, Lajko R, Kolbe T . Novel functions of tyrosine kinase 2 in the antiviral defense against murine cytomegalovirus. J Immunol. 2005; 175(6):4000-8. DOI: 10.4049/jimmunol.175.6.4000. View

Rauch I, Rosebrock F, Hainzl E, Heider S, Majoros A, Wienerroither S . Noncanonical Effects of IRF9 in Intestinal Inflammation: More than Type I and Type III Interferons. Mol Cell Biol. 2015; 35(13):2332-43. PMC: 4456449. DOI: 10.1128/MCB.01498-14. View

Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W . Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993; 75(2):263-74. DOI: 10.1016/0092-8674(93)80068-p. View

Lejeune D, Dumoutier L, Constantinescu S, Kruijer W, Schuringa J, Renauld J . Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line. Pathways that are shared with and distinct from IL-10. J Biol Chem. 2002; 277(37):33676-82. DOI: 10.1074/jbc.M204204200. View

Cox J, Kljavin N, Ota N, Leonard J, Roose-Girma M, Diehl L . Opposing consequences of IL-23 signaling mediated by innate and adaptive cells in chemically induced colitis in mice. Mucosal Immunol. 2011; 5(1):99-109. DOI: 10.1038/mi.2011.54. View

Wiles S, Clare S, Harker J, Huett A, Young D, Dougan G . Organ specificity, colonization and clearance dynamics in vivo following oral challenges with the murine pathogen Citrobacter rodentium. Cell Microbiol. 2004; 6(10):963-72. DOI: 10.1111/j.1462-5822.2004.00414.x. View

10.

Gibson D, Montero M, Ropeleski M, Bergstrom K, Ma C, Ghosh S . Interleukin-11 reduces TLR4-induced colitis in TLR2-deficient mice and restores intestinal STAT3 signaling. Gastroenterology. 2010; 139(4):1277-88. DOI: 10.1053/j.gastro.2010.06.057. View

11.

Rendon J, Li X, Akhtar S, Choudhry M . Interleukin-22 modulates gut epithelial and immune barrier functions following acute alcohol exposure and burn injury. Shock. 2012; 39(1):11-8. PMC: 3526677. DOI: 10.1097/SHK.0b013e3182749f96. View

12.

Smith C, Arvedson T, Cooke K, Dickmann L, Forte C, Li H . IL-22 regulates iron availability in vivo through the induction of hepcidin. J Immunol. 2013; 191(4):1845-55. DOI: 10.4049/jimmunol.1202716. View

13.

Kamada N, Seo S, Chen G, Nunez G . Role of the gut microbiota in immunity and inflammatory disease. Nat Rev Immunol. 2013; 13(5):321-35. DOI: 10.1038/nri3430. View

14.

Vielnascher R, Hainzl E, Leitner N, Rammerstorfer M, Popp D, Witalisz A . Conditional ablation of TYK2 in immunity to viral infection and tumor surveillance. Transgenic Res. 2014; 23(3):519-29. DOI: 10.1007/s11248-014-9795-y. View

15.

Minegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, Tsuchiya S . Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity. 2006; 25(5):745-55. DOI: 10.1016/j.immuni.2006.09.009. View

16.

Ubel C, Graser A, Koch S, Rieker R, Lehr H, Muller M . Role of Tyk-2 in Th9 and Th17 cells in allergic asthma. Sci Rep. 2014; 4:5865. PMC: 4127519. DOI: 10.1038/srep05865. View

17.

Maxwell J, Viney J . Overview of mouse models of inflammatory bowel disease and their use in drug discovery. Curr Protoc Pharmacol. 2012; Chapter 5:Unit5.57. DOI: 10.1002/0471141755.ph0557s47. View

18.

Behnsen J, Jellbauer S, Wong C, Edwards R, George M, Ouyang W . The cytokine IL-22 promotes pathogen colonization by suppressing related commensal bacteria. Immunity. 2014; 40(2):262-73. PMC: 3964146. DOI: 10.1016/j.immuni.2014.01.003. View

19.

Ito R, Shin-Ya M, Kishida T, Urano A, Takada R, Sakagami J . Interferon-gamma is causatively involved in experimental inflammatory bowel disease in mice. Clin Exp Immunol. 2006; 146(2):330-8. PMC: 1942055. DOI: 10.1111/j.1365-2249.2006.03214.x. View

20.

Berry D, Schwab C, Milinovich G, Reichert J, Ben Mahfoudh K, Decker T . Phylotype-level 16S rRNA analysis reveals new bacterial indicators of health state in acute murine colitis. ISME J. 2012; 6(11):2091-106. PMC: 3475367. DOI: 10.1038/ismej.2012.39. View