STAT3在Con A引起肝炎反應中所扮演的角色的研究
The Role of STAT3 in Con A-induced Hepatitis
Date Issued
2005
Date
2005
Author(s)
Lee, Wei
DOI
en-US
Abstract
STAT3 is an essential molecule for the initiation of liver development and regeneration. However the role of STAT3 in liver damage remains unclear. In order to characterize the role of STAT3 in concanavalin A (Con A)-induced model of immune-mediated hepatitis, ST3KO mice were used. After Con A treatment, reduced serum ALT/AST levels, liver injury, apoptosis and high-dose-induced lethality were observed in ST3KO mice as opposed to WT mice, suggesting that STAT3 had a pro-apoptotic role in hepatocytes in Con A-induced hepatitis.
The mechanism of ST3KO mice resistant to Con A-induced hepatitis was further studied. First of all, the percentage and numbers of IHLs, including CD4+ T, NKT, granulocytes and kupffer cells were comparable in WT and ST3KO mice before and after Con A treatment. Secondly, mRNA levels in the liver and protein levels in the serum of pro-inflammatory cytokines such as IL-4, IFN-γ and TNF-α and anti-inflammatory cytokines such as IL-6 and IL-10 were similar between WT and ST3KO mice after Con A treatment. These findings suggested that the recruitment of effector cells to liver and the production and release of cytokines were normal in the absence of STAT3. In line with these results, similar severity of pathology was observed in the spleen, where STAT3 was not deleted. These results suggested that lymphocytes of ST3KO mice were functional.
To investigate if the impaired Con A-induced hepatitis was due to resistance of cytokine-induced apoptosis in the hepatocytes lacking STAT3, primary hepatocytes were incubated with different apoptosis-inducing cytokines in vitro. Decreased TNF-α/Actinomycin D-induced apoptosis was found in STAT3 knockout hepatocytes. Furthermore, IL-6-mediated enhancement of TNF-α/Actinomycin D-induced apoptosis was completely blocked in the absence of STAT3.
Interestingly, the levels of SOCS molecules were dysregulated in the liver of ST3KO mice after Con A treatment. Impaired SOCS3 and prolonged SOCS1 induction were detected in ST3KO mice, implying these atypical SOCS production might be affecting cytokine signaling and contribute to impaired Con A-induced hepatitis in ST3KO mice.
Taken together, these results suggested that STAT3 is a positive regulator for Con A-induced hepatitis by regulating the response through IL-6-STAT3 signaling to enhance TNF-α-induced apoptosis. One of the mechanisms is through its downstream targets such as SOCS1/SOCS3 to regulate cytokine responses.
Subjects
肝炎
STAT3
Con A
hepatitis
SDGs
Type
other
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