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 language | English (US) |
|---|---|
| Pages (from-to) | 99-108 |
| Number of pages | 10 |
| Journal | Journal of Autoimmunity |
| Volume | 51 |
| DOIs | |
| State | Published - 2014 |
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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 journal › Article
}
TY - JOUR
T1 - Distinct from its canonical effects, deletion of IL-12p40 induces cholangitis and fibrosis in interleukin-2Rα-/- mice
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
N2 - 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.
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.
KW - Effector memory cells
KW - Fibrosis
KW - IFN-γ
KW - IL-12p40
KW - Primary biliary cirrhosis
UR - http://www.scopus.com/inward/record.url?scp=84901271022&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84901271022&partnerID=8YFLogxK
U2 - 10.1016/j.jaut.2014.02.009
DO - 10.1016/j.jaut.2014.02.009
M3 - Article
VL - 51
SP - 99
EP - 108
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
SN - 0896-8411
ER -