Critical Role of CREBH-Mediated Induction of Transforming Growth Factor β2 by Hepatitis C Virus Infection in Fibrogenic Responses in Hepatic Stellate Cells
Critical Role of CREBH-Mediated Induction of Transforming Growth Factor β2 by Hepatitis C Virus Infection in Fibrogenic Responses in Hepatic Stellate Cells
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DOI：
10.1002/hep.29319
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发表时间：
2017-11-01
期刊：
影响因子：
13.5
通讯作者：
Suzuki, Tetsuro
中科院分区：
文献类型：
--
作者：
Chida, Takeshi;Ito, Masahiko;Suzuki, Tetsuro
丙型肝炎病毒（HCV）是导致肝纤维化的主要原因之一，其诱导肝纤维化的机制尚不完全清楚。我们研究了转化生长因子β（TGF-β），特别是TGF-β 2的转录上调，这是通过激活肝脏富集的转录因子cAMP反应元件结合蛋白介导的，肝细胞特异性（CREBH）由HCV感染触发，其功能意义的诱导促纤维化表型的HCV感染的细胞与肝星状细胞（HSC）的相互作用。与TGF-β 1相比，HCV感染后TGF-β 2 mRNA的表达诱导更快，水平更高。丙型肝炎患者血清TGF-β 2水平高于健康人，并与肝纤维化分期F0-F2呈正相关。TGF-β 2启动子活性分别通过CREBH的沉默和过表达而降低和增加。在TGF-β 2启动子中鉴定了CREBH识别位点。凝胶迁移率变化和染色质免疫沉淀分别显示CREBH与启动子的结合及其在表达HCV Core-NS 2的细胞中的增加。在HCV感染的嵌合小鼠与人肝和表达HCV蛋白的细胞中可检测到CREBH的活性形式。在CREBH空突变小鼠模型中进一步证实了CREBH参与HCV诱导的纤维化反应。使用HCV感染的细胞和HSC的共培养物评估纤维化表型。TGF-β 2或CREBH沉默可阻止共培养物中纤维化因子和TGF-β 1表达的增加。结论：CREBH是HCV感染细胞中TGF-β 2转录的关键正调控因子。从感染细胞释放的TGF-β 2可能有助于通过其自身的信号传导途径以自分泌方式交叉诱导TGF-β，导致邻近HSC中纤维化反应的增加。
Mechanisms of hepatic fibrogenesis induced by hepatitis C virus (HCV), one of the leading causes of liver fibrosis, are not fully understood. We studied transcriptional up-regulation of transforming growth factor beta (TGF-beta), especially TGF-beta 2, which is mediated by activation of liver-enriched transcription factor cAMP-responsive element-binding protein, hepatocyte specific (CREBH) triggered by HCV infection and its functional significance for induction of profibrogenic phenotypes by interaction of HCV-infected cells with hepatic stellate cells (HSCs). Compared to TGF-beta 1, expression of TGF-beta 2 mRNA was induced faster and to a higher level upon HCV infection. Serum TGF-beta 2 levels in hepatitis C patients were higher compared to those in healthy individuals and were positively correlated with hepatic fibrosis stages F0-F2. TGF-beta 2 promoter activity was decreased and increased, respectively, by silencing and overexpression of CREBH. CREBH recognition sites were identified in the TGF-beta 2 promoter. CREBH binding to the promoter and its increase in cells expressing HCV Core-NS2 were shown by gel mobility shift and chromatin immunoprecipitation, respectively. The active form of CREBH was detectable in HCV-infected chimeric mice with human livers and cells expressing HCV proteins. Involvement of CREBH in HCV-induced fibrogenic response was further demonstrated in the CREBH null-mutant mouse model. Fibrogenic phenotypes were assessed using co-cultures of HCV-infected cells and HSCs. Expressions of fibrogenic factors and TGF-beta 1 increasing in the co-cultures was prevented by TGF-beta 2- or CREBH silencing. Conclusion: CREBH was identified as a key positive regulator of TGF-beta 2 transcription in HCV-infected cells. TGF-beta 2 released from infected cells potentially contributes to cross-induction of TGF-beta in an autocrine manner through its own signaling pathway, leading to an increase in fibrogenic responses in adjacent HSCs.