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High susceptibility to liver injury in IL‐27 p28 conditional knockout mice involves intrinsic interferon‐γ dysregulation of CD4+ T cells

Interleukin (IL)‐27, a newly discovered IL‐12 family cytokine, is composed of p28 and EBI3. In this study, conditional knockout mice were generated to delete p28 specifically in dendritic cells (DCs). We demonstrated that in the absence of DC‐derived p28, these mice were highly susceptible to both l... Full description

Journal Title: Hepatology April 2013, Vol.57(4), pp.1620-1631
Main Author: Zhang, Song
Other Authors: Liang, Ruifang , Luo, Wei , Liu, Chang , Wu, Xiaoli , Gao, Yanan , Hao, Jianlei , Cao, Guangchao , Chen, Xi , Wei, Jun , Xia, Siyuan , Li, Zheng , Wen, Ti , Wu, Yunyun , Zhou, Xinglong , Wang, Puyue , Zhao, Liqing , Wu, Zhengzhou , Xiong, Sidong , Gao, Xiaoming , Gao, Xiang , Chen, Yongyan , Ge, Qing , Tian, Zhigang , Yin, Zhinan
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 0270-9139 ; E-ISSN: 1527-3350 ; DOI: 10.1002/hep.26166
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recordid: wj10.1002/hep.26166
title: High susceptibility to liver injury in IL‐27 p28 conditional knockout mice involves intrinsic interferon‐γ dysregulation of CD4+ T cells
format: Article
creator:
  • Zhang, Song
  • Liang, Ruifang
  • Luo, Wei
  • Liu, Chang
  • Wu, Xiaoli
  • Gao, Yanan
  • Hao, Jianlei
  • Cao, Guangchao
  • Chen, Xi
  • Wei, Jun
  • Xia, Siyuan
  • Li, Zheng
  • Wen, Ti
  • Wu, Yunyun
  • Zhou, Xinglong
  • Wang, Puyue
  • Zhao, Liqing
  • Wu, Zhengzhou
  • Xiong, Sidong
  • Gao, Xiaoming
  • Gao, Xiang
  • Chen, Yongyan
  • Ge, Qing
  • Tian, Zhigang
  • Yin, Zhinan
subjects:
  • Gamma -Interferon
  • Injuries
  • Hepatocytes
  • Natural Killer Cells
  • Mrna
  • Hepatitis
  • Dendritic Cells
  • Interleukin 12
  • Cd4 Antigen
  • Concanavalin A
  • Interleukin 27
  • Lymphocytes T
  • Liver
  • Development, Aging & Organ Systems
ispartof: Hepatology, April 2013, Vol.57(4), pp.1620-1631
description: Interleukin (IL)‐27, a newly discovered IL‐12 family cytokine, is composed of p28 and EBI3. In this study, conditional knockout mice were generated to delete p28 specifically in dendritic cells (DCs). We demonstrated that in the absence of DC‐derived p28, these mice were highly susceptible to both low and higher concentrations of concanavalin A (ConA) (5 mg/kg or 10 mg/kg), with extremely early and steady high levels of interferon‐γ (IFN‐γ) in sera. Neutralizing IFN‐γ prevented ConA‐induced liver damage in these mice, indicating a critical role of IFN‐γ in this pathological process. Interestingly, the main source of the increased IFN‐γ in mice was CD4 T cells, but not natural killer T (NKT) cells. Depletion of CD4, but not NK1.1, cells completely abolished liver damage, whereas transferring CD4 T cells from mice, but not from wild‐type mice or ‐‐γ double knockout mice to CD4 mice, restored the increased liver damage. Further studies defined higher levels of IFN‐γ and T‐bet messenger RNA in naïve CD4 T cells from mice, and these CD4 T cells were highly responsive to both low and higher concentrations of anti‐CD3, indicating a programmed functional alternation of CD4 T cells. : We provide a unique model for studying the pathology of CD4 T cell–mediated liver injury and reveal a novel function of DC‐derived p28 on ConA‐induced fulminant hepatitis through regulation of the intrinsic ability for IFN‐γ production by CD4 T cells. (H 2013)
language: eng
source:
identifier: ISSN: 0270-9139 ; E-ISSN: 1527-3350 ; DOI: 10.1002/hep.26166
fulltext: fulltext
issn:
  • 0270-9139
  • 02709139
  • 1527-3350
  • 15273350
url: Link


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titleHigh susceptibility to liver injury in IL‐27 p28 conditional knockout mice involves intrinsic interferon‐γ dysregulation of CD4+ T cells
creatorZhang, Song ; Liang, Ruifang ; Luo, Wei ; Liu, Chang ; Wu, Xiaoli ; Gao, Yanan ; Hao, Jianlei ; Cao, Guangchao ; Chen, Xi ; Wei, Jun ; Xia, Siyuan ; Li, Zheng ; Wen, Ti ; Wu, Yunyun ; Zhou, Xinglong ; Wang, Puyue ; Zhao, Liqing ; Wu, Zhengzhou ; Xiong, Sidong ; Gao, Xiaoming ; Gao, Xiang ; Chen, Yongyan ; Ge, Qing ; Tian, Zhigang ; Yin, Zhinan
ispartofHepatology, April 2013, Vol.57(4), pp.1620-1631
identifier
descriptionInterleukin (IL)‐27, a newly discovered IL‐12 family cytokine, is composed of p28 and EBI3. In this study, conditional knockout mice were generated to delete p28 specifically in dendritic cells (DCs). We demonstrated that in the absence of DC‐derived p28, these mice were highly susceptible to both low and higher concentrations of concanavalin A (ConA) (5 mg/kg or 10 mg/kg), with extremely early and steady high levels of interferon‐γ (IFN‐γ) in sera. Neutralizing IFN‐γ prevented ConA‐induced liver damage in these mice, indicating a critical role of IFN‐γ in this pathological process. Interestingly, the main source of the increased IFN‐γ in mice was CD4 T cells, but not natural killer T (NKT) cells. Depletion of CD4, but not NK1.1, cells completely abolished liver damage, whereas transferring CD4 T cells from mice, but not from wild‐type mice or ‐‐γ double knockout mice to CD4 mice, restored the increased liver damage. Further studies defined higher levels of IFN‐γ and T‐bet messenger RNA in naïve CD4 T cells from mice, and these CD4 T cells were highly responsive to both low and higher concentrations of anti‐CD3, indicating a programmed functional alternation of CD4 T cells. : We provide a unique model for studying the pathology of CD4 T cell–mediated liver injury and reveal a novel function of DC‐derived p28 on ConA‐induced fulminant hepatitis through regulation of the intrinsic ability for IFN‐γ production by CD4 T cells. (H 2013)
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subjectGamma -Interferon ; Injuries ; Hepatocytes ; Natural Killer Cells ; Mrna ; Hepatitis ; Dendritic Cells ; Interleukin 12 ; Cd4 Antigen ; Concanavalin A ; Interleukin 27 ; Lymphocytes T ; Liver ; Development, Aging & Organ Systems;
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titleHigh susceptibility to liver injury in IL‐27 p28 conditional knockout mice involves intrinsic interferon‐γ dysregulation of CD4+ T cells
descriptionInterleukin (IL)‐27, a newly discovered IL‐12 family cytokine, is composed of p28 and EBI3. In this study, conditional knockout mice were generated to delete p28 specifically in dendritic cells (DCs). We demonstrated that in the absence of DC‐derived p28, these mice were highly susceptible to both low and higher concentrations of concanavalin A (ConA) (5 mg/kg or 10 mg/kg), with extremely early and steady high levels of interferon‐γ (IFN‐γ) in sera. Neutralizing IFN‐γ prevented ConA‐induced liver damage in these mice, indicating a critical role of IFN‐γ in this pathological process. Interestingly, the main source of the increased IFN‐γ in mice was CD4 T cells, but not natural killer T (NKT) cells. Depletion of CD4, but not NK1.1, cells completely abolished liver damage, whereas transferring CD4 T cells from mice, but not from wild‐type mice or ‐‐γ double knockout mice to CD4 mice, restored the increased liver damage. Further studies defined higher levels of IFN‐γ and T‐bet messenger RNA in naïve CD4 T cells from mice, and these CD4 T cells were highly responsive to both low and higher concentrations of anti‐CD3, indicating a programmed functional alternation of CD4 T cells. : We provide a unique model for studying the pathology of CD4 T cell–mediated liver injury and reveal a novel function of DC‐derived p28 on ConA‐induced fulminant hepatitis through regulation of the intrinsic ability for IFN‐γ production by CD4 T cells. (H 2013)
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authorZhang, Song ; Liang, Ruifang ; Luo, Wei ; Liu, Chang ; Wu, Xiaoli ; Gao, Yanan ; Hao, Jianlei ; Cao, Guangchao ; Chen, Xi ; Wei, Jun ; Xia, Siyuan ; Li, Zheng ; Wen, Ti ; Wu, Yunyun ; Zhou, Xinglong ; Wang, Puyue ; Zhao, Liqing ; Wu, Zhengzhou ; Xiong, Sidong ; Gao, Xiaoming ; Gao, Xiang ; Chen, Yongyan ; Ge, Qing ; Tian, Zhigang ; Yin, Zhinan
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abstractInterleukin (IL)‐27, a newly discovered IL‐12 family cytokine, is composed of p28 and EBI3. In this study, conditional knockout mice were generated to delete p28 specifically in dendritic cells (DCs). We demonstrated that in the absence of DC‐derived p28, these mice were highly susceptible to both low and higher concentrations of concanavalin A (ConA) (5 mg/kg or 10 mg/kg), with extremely early and steady high levels of interferon‐γ (IFN‐γ) in sera. Neutralizing IFN‐γ prevented ConA‐induced liver damage in these mice, indicating a critical role of IFN‐γ in this pathological process. Interestingly, the main source of the increased IFN‐γ in mice was CD4 T cells, but not natural killer T (NKT) cells. Depletion of CD4, but not NK1.1, cells completely abolished liver damage, whereas transferring CD4 T cells from mice, but not from wild‐type mice or ‐‐γ double knockout mice to CD4 mice, restored the increased liver damage. Further studies defined higher levels of IFN‐γ and T‐bet messenger RNA in naïve CD4 T cells from mice, and these CD4 T cells were highly responsive to both low and higher concentrations of anti‐CD3, indicating a programmed functional alternation of CD4 T cells. : We provide a unique model for studying the pathology of CD4 T cell–mediated liver injury and reveal a novel function of DC‐derived p28 on ConA‐induced fulminant hepatitis through regulation of the intrinsic ability for IFN‐γ production by CD4 T cells. (H 2013)
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pubWiley Subscription Services, Inc., A Wiley Company
doi10.1002/hep.26166
pages1620-1631
date2013-04