| First Author | Zhang S | Year | 2013 |
| Journal | Hepatology | Volume | 57 |
| Issue | 4 | Pages | 1620-31 |
| PubMed ID | 23175475 | Mgi Jnum | J:272195 |
| Mgi Id | MGI:6281305 | Doi | 10.1002/hep.26166 |
| Citation | Zhang S, et al. (2013) High susceptibility to liver injury in IL-27 p28 conditional knockout mice involves intrinsic interferon-gamma dysregulation of CD4+ T cells. Hepatology 57(4):1620-31 |
| abstractText | UNLABELLED: 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-gamma (IFN-gamma) in sera. Neutralizing IFN-gamma prevented ConA-induced liver damage in these mice, indicating a critical role of IFN-gamma in this pathological process. Interestingly, the main source of the increased IFN-gamma 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-gamma(-/-) double knockout mice to CD4(-/-) mice, restored the increased liver damage. Further studies defined higher levels of IFN-gamma and T-bet messenger RNA in naive 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. CONCLUSION: 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-gamma production by CD4+ T cells. |
