RGD Reference Report - STAT4 knockout mice are more susceptible to concanavalin A-induced T-cell hepatitis. - Rat Genome Database

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STAT4 knockout mice are more susceptible to concanavalin A-induced T-cell hepatitis.

Authors: Wang, Yan  Feng, Dechun  Wang, Hua  Xu, Ming-Jiang  Park, Ogyi  Li, Yongmei  Gao, Bin 
Citation: Wang Y, etal., Am J Pathol. 2014 Jun;184(6):1785-94. doi: 10.1016/j.ajpath.2014.02.023. Epub 2014 Apr 13.
RGD ID: 25671417
Pubmed: PMID:24731448   (View Abstract at PubMed)
PMCID: PMC4044716   (View Article at PubMed Central)
DOI: DOI:10.1016/j.ajpath.2014.02.023   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Chemical and Drug Induced Liver Injury severityISOStat4 (Mus musculus)25671417; 25671417protein:increased phosphorylation:liver and inflammatory cell (mouse)RGD 
Chemical and Drug Induced Liver Injury severityIEP 25671417protein:increased phosphorylation:liver and inflammatory cell (mouse)RGD 
viral hepatitis susceptibilityIEP 25671417protein:increased phosphorylation:liver and inflammatory cell (human)RGD 
viral hepatitis susceptibilityISOSTAT4 (Homo sapiens)25671417; 25671417protein:increased phosphorylation:liver and inflammatory cell (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Stat4  (signal transducer and activator of transcription 4)

Genes (Mus musculus)
Stat4  (signal transducer and activator of transcription 4)

Genes (Homo sapiens)
STAT4  (signal transducer and activator of transcription 4)


Additional Information