title: High susceptibility to liver injury in IL-27 p28 conditional knockout mice involves intrinsic interferon-γ dysregulation of CD4+ T cells.
abstract: Interleukin (IL)-27, a newly discovered IL-12 family cytokine, is composed of p28 and EBI3. In this study, CD11c-p28(f/f) 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 CD11c-p28(f/f) 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 CD11c-p28(f/f) mice, but not from wild-type mice or CD11c-p28(f/f) -IFN-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 CD11c-p28(f/f) 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Song
authors.initials: S
authors.lastname: Zhang
authors.forename: Ruifang
authors.initials: R
authors.lastname: Liang
authors.forename: Wei
authors.initials: W
authors.lastname: Luo
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wu
authors.forename: Yanan
authors.initials: Y
authors.lastname: Gao
authors.forename: Jianlei
authors.initials: J
authors.lastname: Hao
authors.forename: Guangchao
authors.initials: G
authors.lastname: Cao
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.forename: Siyuan
authors.initials: S
authors.lastname: Xia
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.forename: Ti
authors.initials: T
authors.lastname: Wen
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Wu
authors.forename: Xinglong
authors.initials: X
authors.lastname: Zhou
authors.forename: Puyue
authors.initials: P
authors.lastname: Wang
authors.forename: Liqing
authors.initials: L
authors.lastname: Zhao
authors.forename: Zhengzhou
authors.initials: Z
authors.lastname: Wu
authors.forename: Sidong
authors.initials: S
authors.lastname: Xiong
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Gao
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Yongyan
authors.initials: Y
authors.lastname: Chen
authors.forename: Qing
authors.initials: Q
authors.lastname: Ge
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Tian
authors.forename: Zhinan
authors.initials: Z
authors.lastname: Yin
mesh_terms: D000818:Animals; D039521:CD11c Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology* / Q000503:physiopathology*; D003208:Concanavalin A / Q000009:adverse effects*; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology*; D020381:Interleukin-17 / Q000235:genetics / Q000502:physiology; D007694:Killer Cells, Natural / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout
chemical_list: D039521:CD11c Antigen; D020381:Interleukin-17; D003208:Concanavalin A; D007371:Interferon-gamma