STAT1及STAT3在Con A引起肝炎反應所扮演的角色研究

The role of STAT1 or STAT3 in Con A-induced hepatitis

關珞(Lo Kuan)

指導教授 ： 李建國

國立臺灣大學/醫學院/免疫學研究所/碩士(2004年)

https://doi.org/10.6342/NTU.2004.01547

摘要

利用Con A 注射在小鼠引發嚴重肝臟病變是研究人類肝炎的一個很好動物模式。即使這個動物模式已經發展了數十年，但是它真正引發肝病變的機制仍未清楚。在此我們利用傳統的STAT1基因剔除鼠（ST1KO）以及只剔除肝臟細胞的STAT3基因（ST3KO）的老鼠來研究STAT1和STAT3在Con A引發的肝炎模式中所扮演的角色。
Con A的刺激下正常老鼠肝臟細胞中的STAT1以及STAT3都會短暫的被活化。雖然，STAT3被活化的程度在ST1KO的老鼠以及正常的老鼠是沒有太大的差別，然而STAT1在ST3KO的老鼠裡活化的程度卻比正常的老鼠高。有趣的是，在 Con A的刺激下在缺少STAT1或者STAT3的老鼠中都只產生輕微的肝臟病變，這兩種老鼠血清裡的ALT 以及AST都較正常的老鼠為低，從肝臟切片中我們也發現沒有或較少的肝臟受損，或者肝臟細胞的caspase 3活性較正常的老鼠低。
接著我們想進一步研究這兩種mutant老鼠抵抗Con A引發肝炎的機制。首先，我們發現在正常老鼠與ST3KO老鼠中肝臟裡的各種淋巴球（IHL）數目，如natural killer T（NKT）細胞，CD4+ T細胞，以及顆粒球細胞，在Con A刺激前或者刺激後都相當類似，此結果暗示肝臟細胞的STAT3被剔除後並不影響effector細胞被徵召回肝臟中。第二，Con A刺激後血清中促進發炎的細胞激素知, 如IFN-

關鍵字

肝炎模式 ； 訊息傳遞 ； 發炎 ； 肝臟

並列摘要

Concanavalin A (Con A)-induced severe liver damage in mice is considered a model for human hepatitis. Although this model has been established for decades, the underlying mechanisms are still not fully understood. By using STAT1 traditional knockout mice and conditional knockout mice lacking STAT3 in the liver, the roles of STAT1 and STAT3, two important transcriptional factors, in Con A-induced hepatitis are investigated.
Both STAT1 and STAT3 are transiently activated in the hepatocytes of wild-type (WT) mice by tyrosine phosphorylation following Con A administration. While levels of STAT3 activation in STAT1 knockout (ST1KO) mice are comparable to that of Wild-type (WT) mice, STAT1 activation, however, is enhanced in STAT3 conditional knockout (ST3KO) mice. Interestingly, Con A-induced hepatitis is greatly impaired in mice either lacking STAT1 or STAT3 in the liver, with reduced serum alanine transaminase (ALT) and asparate transaminase (AST), less severe liver damage in histological sections, and decreased caspase-3 activity in the Con A-treated hepatocytes.
The mechanisms of mutant mice resistant to Con A-induced hepatitis are further explored. First of all, the number of intrahepatic leukocytes (IHLs), including natural killer T (NKT), CD4+ T cells, and granulocytes are found to be similar between WT and ST3KO mice before and after Con A treatment, suggesting that the recruitment of these effector cells to liver is normal in the absence of STAT3. Secondly, profiles of serum pro-inflammatory cytokines such as IFN-

並列關鍵字

SOCS1 ； NKT ； IHL ； STAT3 ； STAT1 ； ALT ； Con A-induced hepatitis ； SOCS3 ； AST

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