title: Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS.
abstract: T cell-mediated fulminant hepatitis is a life-threatening event for which the underlying mechanism is not fully understood. Injection of concanavalin A (Con A) into mice recapitulates the histological and pathological sequelae of T cell-mediated hepatitis. In this model, both signal transducer and activator of transcription factor 1 (STAT1) and STAT3 are activated in the liver. Disruption of the STAT1 gene by way of genetic knockout attenuates liver injury, suppresses CD4(+) and NK T cell activation, and downregulates expression of proapoptotic interferon regulatory factor-1 protein and suppressor of cytokine signaling-1 (SOCS1), but enhances STAT3 activation and STAT3-controlled antiapoptotic signals. Studies from IFN-gamma-deficient mice indicate that IFN-gamma not only is the major cytokine responsible for STAT1 activation but also partially accounts for STAT3 activation. Moreover, downregulation of STAT3 activation in IL-6-deficient mice is associated with decreased STAT3-controlled antiapoptotic signals and expression of SOCS3, but upregulation of STAT1 activation and STAT1-induced proapoptotic signals and exacerbation of liver injury. Taken together, these findings suggest that STAT1 plays a harmful role in Con A-mediated hepatitis by activation of CD4(+) and NK T cells and directly inducing hepatocyte death, whereas STAT3 protects against liver injury by suppression of IFN-gamma signaling and induction of antiapoptotic protein Bcl-X(L). STAT1 and STAT3 in hepatocytes also negatively regulate one another through the induction of SOCS.
authors.affiliation: Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Hong
authors.forename: Barbara
authors.initials: B
authors.lastname: Jaruga
authors.forename: Won Ho
authors.initials: WH
authors.lastname: Kim
authors.forename: Svetlana
authors.initials: S
authors.lastname: Radaeva
authors.forename: Osama N
authors.initials: ON
authors.lastname: El-Assal
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Tian
authors.forename: Van-Anh
authors.initials: VA
authors.lastname: Nguyen
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003208:Concanavalin A / Q000633:toxicity; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019693:Hepatitis, Autoimmune / Q000209:etiology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013601:T-Lymphocytes / Q000276:immunology*; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C108944:SOCS1 protein, human; C106644:SOCS3 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C491590:Socs1 protein, mouse; C491411:Socs3 protein, mouse; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D003208:Concanavalin A; D007371:Interferon-gamma