Distinct from its canonical effects, deletion of IL-12p40 induces cholangitis and fibrosis in interleukin-2Rα-/- mice

Yuan Yao, Wei Yang, Yan Qing Yang, Hong Di Ma, Fang Ting Lu, Liang Li, Yan Yan Tao, Koichi Tsuneyama, Weici Zhang, Scott Friedman, M. Eric Gershwin, Zhe Xiong Lian

Research output: Contribution to journalArticle

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Abstract

The IL-12 family modulates T cell mediated autoimmune diseases and GWAS in PBC have suggested a critical role of IL-12 and its subunits in modulating portal inflammation. We have taken advantage of an aggressive model of portal inflammation and colitis in IL-2Rα-/- mice to study the specific role of IL-12 and, in particular, the immunobiology of p40-/-IL-2Rα-/- mice. Colonies of IL-2Rα+/-, IL-2Rα-/- and p40-/-IL-2Rα-/- mice were studied for the natural history of immunopathology in liver and colon using histology and immunohistochemistry. Further, to focus on mechanisms, liver, spleen and mesenteric lymph node flow cytometry was employed to identify specific phenotypes; cytokine analysis on inflammatory cell populations was compared between groups. Finally, Real-Time PCR was used to focus on the genes involved in hepatic fibrosis. Surprisingly, p40-/-IL-2Rα-/- mice manifest more severe portal inflammation and bile duct damage, including signs of portal hypertension and liver fibrosis, but a significant reduction in colitis. Indeed, p40-/-IL-2Rα-/- mice reveal a profound hepatic CD8+ T cell infiltrate, whose major component are effector memory cells as well as enhanced hepatic Th1 but reduced Th17 responses. These observations were confirmed by Real-Time PCR analysis of fibrosis-related genes in the liver. Distinct from its canonical effects, IL-12p40 plays a critical role in autoimmune cholangitis, including hepatic fibrosis. These data take on striking significance for any proposed human trials that modulate the IL-12p40 pathway in human PBC.

Original languageEnglish (US)
Pages (from-to)99-108
Number of pages10
JournalJournal of Autoimmunity
Volume51
DOIs
StatePublished - 2014

Fingerprint

Interleukin-12 Subunit p40
Cholangitis
Interleukins
Fibrosis
Liver
Interleukin-12
Colitis
Inflammation
Real-Time Polymerase Chain Reaction
T-Lymphocytes
Genome-Wide Association Study
Portal Hypertension
Bile Ducts
Natural History
Liver Cirrhosis
Genes
Autoimmune Diseases
Histology
Flow Cytometry
Colon

Keywords

  • Effector memory cells
  • Fibrosis
  • IFN-γ
  • IL-12p40
  • Primary biliary cirrhosis

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Medicine(all)

Cite this

Distinct from its canonical effects, deletion of IL-12p40 induces cholangitis and fibrosis in interleukin-2Rα-/- mice. / Yao, Yuan; Yang, Wei; Yang, Yan Qing; Ma, Hong Di; Lu, Fang Ting; Li, Liang; Tao, Yan Yan; Tsuneyama, Koichi; Zhang, Weici; Friedman, Scott; Gershwin, M. Eric; Lian, Zhe Xiong.

In: Journal of Autoimmunity, Vol. 51, 2014, p. 99-108.

Research output: Contribution to journalArticle

Yao, Yuan ; Yang, Wei ; Yang, Yan Qing ; Ma, Hong Di ; Lu, Fang Ting ; Li, Liang ; Tao, Yan Yan ; Tsuneyama, Koichi ; Zhang, Weici ; Friedman, Scott ; Gershwin, M. Eric ; Lian, Zhe Xiong. / Distinct from its canonical effects, deletion of IL-12p40 induces cholangitis and fibrosis in interleukin-2Rα-/- mice. In: Journal of Autoimmunity. 2014 ; Vol. 51. pp. 99-108.
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AU - Yao, Yuan

AU - Yang, Wei

AU - Yang, Yan Qing

AU - Ma, Hong Di

AU - Lu, Fang Ting

AU - Li, Liang

AU - Tao, Yan Yan

AU - Tsuneyama, Koichi

AU - Zhang, Weici

AU - Friedman, Scott

AU - Gershwin, M. Eric

AU - Lian, Zhe Xiong

PY - 2014

Y1 - 2014

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AB - The IL-12 family modulates T cell mediated autoimmune diseases and GWAS in PBC have suggested a critical role of IL-12 and its subunits in modulating portal inflammation. We have taken advantage of an aggressive model of portal inflammation and colitis in IL-2Rα-/- mice to study the specific role of IL-12 and, in particular, the immunobiology of p40-/-IL-2Rα-/- mice. Colonies of IL-2Rα+/-, IL-2Rα-/- and p40-/-IL-2Rα-/- mice were studied for the natural history of immunopathology in liver and colon using histology and immunohistochemistry. Further, to focus on mechanisms, liver, spleen and mesenteric lymph node flow cytometry was employed to identify specific phenotypes; cytokine analysis on inflammatory cell populations was compared between groups. Finally, Real-Time PCR was used to focus on the genes involved in hepatic fibrosis. Surprisingly, p40-/-IL-2Rα-/- mice manifest more severe portal inflammation and bile duct damage, including signs of portal hypertension and liver fibrosis, but a significant reduction in colitis. Indeed, p40-/-IL-2Rα-/- mice reveal a profound hepatic CD8+ T cell infiltrate, whose major component are effector memory cells as well as enhanced hepatic Th1 but reduced Th17 responses. These observations were confirmed by Real-Time PCR analysis of fibrosis-related genes in the liver. Distinct from its canonical effects, IL-12p40 plays a critical role in autoimmune cholangitis, including hepatic fibrosis. These data take on striking significance for any proposed human trials that modulate the IL-12p40 pathway in human PBC.

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KW - Fibrosis

KW - IFN-γ

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KW - Primary biliary cirrhosis

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