title: STAT4 knockout mice are more susceptible to concanavalin A-induced T-cell hepatitis.
abstract: STAT4, which is activated mainly by IL-12, promotes inflammatory responses by inducing Th1 and Th2 cytokines. Recent genome-wide association studies indicate that STAT4 gene variants are associated with risk of various types of liver diseases, but how STAT4 contributes to liver disease pathogenesis remains obscure. In this study, STAT4 activation was detected in liver immune cells from patients with viral hepatitis and autoimmune hepatitis, as well as in a mouse model of concanavalin A (Con A)-induced hepatitis. Such STAT4 activation was detected mainly in T cells, natural killer T cells, and macrophages and Kupffer cells, and was diminished in Il12a(-/-) and Il12b(-/-) mice. As expected, disruption of the Stat4 gene reduced production of Th1 and Th2 cytokines, but surprisingly exacerbated Con A-induced liver injury. Similarly, disruption of Il12a or Il12b also augmented Con A-induced hepatocellular damage. Further studies showed that hepatic natural killer T (NKT) cells from Con A-treated Stat4(-/-) mice had higher levels of FasL expression and increased cytotoxicity against hepatocytes than those from Con A-treated WT mice. In vitro, blocking FasL attenuated Stat4(-/-) NKT cytotoxicity against hepatocytes. In conclusion, despite up-regulation of proinflammatory cytokines, STAT4 protects against acute T-cell hepatitis, which is mediated by direct or indirect down-regulation of FasL expression on NKT cells.
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland; Department of Infectious Diseases, Peking University First Hospital, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Dechun
authors.initials: D
authors.lastname: Feng
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Ming-Jiang
authors.initials: MJ
authors.lastname: Xu
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Ogyi
authors.initials: O
authors.lastname: Park
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland. Electronic address: bgao@mail.nih.gov.
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
mesh_terms: D000208:Acute Disease; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology* / Q000473:pathology; D003208:Concanavalin A / Q000009:adverse effects* / Q000494:pharmacology; D022781:Hepatocytes / Q000276:immunology* / Q000473:pathology; D053765:Interleukin-12 Subunit p35 / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008934:Mitogens / Q000009:adverse effects* / Q000494:pharmacology; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000473:pathology; D050797:STAT4 Transcription Factor
chemical_list: C508859:Il12a protein, mouse; D053765:Interleukin-12 Subunit p35; D008934:Mitogens; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D003208:Concanavalin A
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