The immunobiology of colitis and cholangitis in interleukin-23p19 and interleukin-17a deleted dominant negative form of transforming growth factor beta receptor type II mice

Yugo Ando, Guo Xiang Yang, Masanobu Tsuda, Kazuhito Kawata, Weici Zhang, Takahiko Nakajima, Koichi Tsuneyama, Patrick S Leung, Zhe Xiong Lian, Kazuichi Okazaki, William M. Ridgway, Gary L. Norman, Aftab A. Ansari, Xiaosong He, Ross L. Coppel, M. Eric Gershwin

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Abstract

Dominant negative form of transforming growth factor beta receptor type II (dnTGFβRII) mice, expressing a dominant negative form of TGFβ receptor II under control of the CD4 promoter, develop autoimmune colitis and cholangitis. Deficiency in interleukin (IL)-12p40 lead to a marked diminution of inflammation in both the colon and the liver. To distinguish whether IL-12p40 mediates protection by the IL-12 or IL-23 pathways, we generated an IL-23p19-/- dnTGFβRII strain deficient in IL-23, but not in IL-12; mice were longitudinally followed for changes in the natural history of disease and immune responses. Interestingly, IL-23p19-/- mice demonstrate dramatic improvement in their colitis, but no changes in biliary pathology; mice also manifest reduced T-helper (Th)17 cell populations and unchanged IFN-γ levels. We submit that the IL-12/Th1 pathway is essential for biliary disease pathogenesis, whereas the IL-23/Th17 pathway mediates colitis. To further assess the mechanism of the IL-23-mediated protection from colitis, we generated an IL-17A-/- dnTGFβRII strain deficient in IL-17, a major effector cytokine produced by IL-23-dependent Th17 cells. Deletion of the IL-17A gene did not affect the severity of either cholangitis or colitis, suggesting that the IL-23/Th17 pathway contributes to colon disease in an IL-17-independent manner. These results affirm that the IL-12/Th1 pathway is critical to biliary pathology in dnTGFβRII mice, whereas colitis is caused by a direct effect of IL-23.

Original languageEnglish (US)
Pages (from-to)1418-1426
Number of pages9
JournalHepatology
Volume56
Issue number4
DOIs
StatePublished - Oct 2012

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Interleukin-23
Cholangitis
Interleukin-17
Interleukins
Colitis
Interleukin-12
Th17 Cells
Colon
Pathology
Critical Pathways
Immune System Diseases
transforming growth factor-beta type II receptor
Cytokines
Inflammation
Liver

ASJC Scopus subject areas

  • Hepatology

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The immunobiology of colitis and cholangitis in interleukin-23p19 and interleukin-17a deleted dominant negative form of transforming growth factor beta receptor type II mice. / Ando, Yugo; Yang, Guo Xiang; Tsuda, Masanobu; Kawata, Kazuhito; Zhang, Weici; Nakajima, Takahiko; Tsuneyama, Koichi; Leung, Patrick S; Lian, Zhe Xiong; Okazaki, Kazuichi; Ridgway, William M.; Norman, Gary L.; Ansari, Aftab A.; He, Xiaosong; Coppel, Ross L.; Gershwin, M. Eric.

In: Hepatology, Vol. 56, No. 4, 10.2012, p. 1418-1426.

Research output: Contribution to journalArticle

Ando, Y, Yang, GX, Tsuda, M, Kawata, K, Zhang, W, Nakajima, T, Tsuneyama, K, Leung, PS, Lian, ZX, Okazaki, K, Ridgway, WM, Norman, GL, Ansari, AA, He, X, Coppel, RL & Gershwin, ME 2012, 'The immunobiology of colitis and cholangitis in interleukin-23p19 and interleukin-17a deleted dominant negative form of transforming growth factor beta receptor type II mice', Hepatology, vol. 56, no. 4, pp. 1418-1426. https://doi.org/10.1002/hep.25803
Ando, Yugo ; Yang, Guo Xiang ; Tsuda, Masanobu ; Kawata, Kazuhito ; Zhang, Weici ; Nakajima, Takahiko ; Tsuneyama, Koichi ; Leung, Patrick S ; Lian, Zhe Xiong ; Okazaki, Kazuichi ; Ridgway, William M. ; Norman, Gary L. ; Ansari, Aftab A. ; He, Xiaosong ; Coppel, Ross L. ; Gershwin, M. Eric. / The immunobiology of colitis and cholangitis in interleukin-23p19 and interleukin-17a deleted dominant negative form of transforming growth factor beta receptor type II mice. In: Hepatology. 2012 ; Vol. 56, No. 4. pp. 1418-1426.
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abstract = "Dominant negative form of transforming growth factor beta receptor type II (dnTGFβRII) mice, expressing a dominant negative form of TGFβ receptor II under control of the CD4 promoter, develop autoimmune colitis and cholangitis. Deficiency in interleukin (IL)-12p40 lead to a marked diminution of inflammation in both the colon and the liver. To distinguish whether IL-12p40 mediates protection by the IL-12 or IL-23 pathways, we generated an IL-23p19-/- dnTGFβRII strain deficient in IL-23, but not in IL-12; mice were longitudinally followed for changes in the natural history of disease and immune responses. Interestingly, IL-23p19-/- mice demonstrate dramatic improvement in their colitis, but no changes in biliary pathology; mice also manifest reduced T-helper (Th)17 cell populations and unchanged IFN-γ levels. We submit that the IL-12/Th1 pathway is essential for biliary disease pathogenesis, whereas the IL-23/Th17 pathway mediates colitis. To further assess the mechanism of the IL-23-mediated protection from colitis, we generated an IL-17A-/- dnTGFβRII strain deficient in IL-17, a major effector cytokine produced by IL-23-dependent Th17 cells. Deletion of the IL-17A gene did not affect the severity of either cholangitis or colitis, suggesting that the IL-23/Th17 pathway contributes to colon disease in an IL-17-independent manner. These results affirm that the IL-12/Th1 pathway is critical to biliary pathology in dnTGFβRII mice, whereas colitis is caused by a direct effect of IL-23.",
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AU - Kawata, Kazuhito

AU - Zhang, Weici

AU - Nakajima, Takahiko

AU - Tsuneyama, Koichi

AU - Leung, Patrick S

AU - Lian, Zhe Xiong

AU - Okazaki, Kazuichi

AU - Ridgway, William M.

AU - Norman, Gary L.

AU - Ansari, Aftab A.

AU - He, Xiaosong

AU - Coppel, Ross L.

AU - Gershwin, M. Eric

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