STAT3在抗病毒反應中所扮演的角色的研究
Other Title
Role of STAT3 in Antiviral Responses
Start Page
1
End Page
57
Date Issued
2011
Date
2011
Author(s)
Advisor
李建國
Abstract
Type I interferons (IFNs) are potent cytokines for innate immunity to combat viral infections. It has been well documented that signal transducer and activator of transcription (STAT) proteins such as STAT1, STAT2, and STAT3 are activated upon IFN-α/β stimulation. While essential roles of STAT1 and STAT2 in type I IFN-mediated antiviral responses are demonstrated in gene-targeting mice, the role of STAT3 remains unclear. Using STAT3KO mouse fibroblasts (MEFs) and primary bone-marrow-derived macrophages (BMMs) lacking STAT3, we demonstrated that IFN-α signals in STAT3KO MEFs or BMMs were enhanced. Both microarray and RT-QPCR analysis revealed that the induction of several IFN-a-inducible antiviral-associated genes was higher in STAT3KO cells than that in wild-type cells in response to IFN-α. Moreover, STAT3KO cells also displayed increased antiviral responses to encephalomyocarditis virus (EMCV) or vesicular stomatitis virus (VSV) infections with increased survival levels and decreased viral titers. STAT3 restoration to STAT3KO MEFs or STAT3 hyper-activation by IL-6 stimulation attenuated the enhanced type I IFN signals and antiviral responses, suggesting that STAT3 negatively regulates these two responses. Surprisingly, STAT3 1-134 a.a. was sufficient to reverse the hyper-antiviral activity. We also found that EMCV infection or TLR agonists stimulation induces the increased level of IFN-α/β in the absence of STAT3 in vitro or in vivo. Additionally, STAT3 might suppress the IFN-β promoter activity upon poly (I:C) treatment and mitochondrial antiviral signaling (MAVS)-mediated signaling pathway. Therefore, at least, two mechanisms might contribute to the enhanced antiviral activity, namely enhanced signaling of type I IFNs and increased IFN-α/β production, in the cells lacking STAT3. Taken together, these results suggest an important and yet previously uncharacterized role of STAT3 in IFN-α/β and TLR-mediated antiviral responses.
在對抗病毒和細菌感染的先天性免疫反應(innate immunity)中，第一型干擾素(type I interferons; type I IFNs)是非常重要的細胞素(cytokine)之一。目前，己經有文獻報告指出IFN-a/b會活化STAT 蛋白質(signal transducer and activator transcription protein)家族中的STAT1，STAT2和STAT3。在基因剔除鼠的研究中證實，STAT1和STAT2對IFN-a/b所引起的抗病毒反應非常重要，但是目前對於STAT3在抗病毒機轉上扮演的角色並不清楚。本研究利用缺乏STAT3的巨噬細胞(macrophage)來探討STAT3在IFN-a/b引起的抗病毒反應中所扮演的角色。和對照組的BMM (bone marrow-derived macrophage)比較起來，在STAT3KO BMM中一些抗病毒相關的基因，例如IRF1(interferon regulatory factor 1)、IRF7 (interferon regulatory factor 7)和OAS (oligoadenylated synthetase)，其表現量經由IFN-a/b所誘導的效果比較差。同樣地，以類似病毒基因結構的poly (I:C)去刺激BMM，也發現IFN-a和PKR基因在STAT3KO的BMM中較對照組的BMM低。最後，本研究也利用Encephalomyocarditis virus (EMCV)這株病毒去感染巨噬細胞，以了解在缺乏STAT3的狀況下，IFN-a在細胞產生抗病毒的能力是否會受到影響。我們發現在低濃度血清的培養環境下，STAT3KO的BMM在受到EMCV感染後,即使在沒有IFN-a的前置處理下，細胞的存活率明顯的上升。然而，受EMCV感染的對照組和STAT3KO的BMM所產生的病毒效價(viral titer)卻是差不多的。相反的，在高濃度血清的培養環境下，受EMCV感染後的STAT3KO的PM，無論有沒有IFN-a 的前置處理，其cytopathic effect (CPE)比對照組細胞都來得嚴重，這些結果暗示著STAT3在IFN-a對於巨噬細胞所引起的抗病毒反應中可能扮演著重要角色。
Subjects
STAT3
IFN
Antiviral response
Publisher
國立臺灣大學
Description
碩士論文
Type
thesis
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