Division of Intractable Diseases, Center for Biomedical Sciences, National Institute of Health, Chungcheongbuk-do 363-951, Korea.
Cell Signal. 2013 Jul;25(7):1635-43. doi: 10.1016/j.cellsig.2013.04.001. Epub 2013 Apr 12.
Hsp47 is a collagen-specific molecular chaperone, whose activity has been implicated in liver fibrosis. In this study, we showed that TRAIL treatment inhibited Hsp47 expression in dose- and time-dependent manners, subsequently leading to the decrease of collagen production in activated human hepatic stellate LX-2 cells. Overexpression of Hsp47 in LX-2 cells acquired resistance for TRAIL-induced collagen reduction and conversely, siRNA suppression of Hsp47 enhanced the decrease of collagen production due to TRAIL treatment. Moreover, we found that Hsp47 expression was under the transcriptional control of heat shock factor (HSF) 1 which is highly located on nucleus in activated human hepatic stellate LX-2 cells. Treatment of LX-2 cells with TRAIL decreased the active trimer formation of HSF1, increased the dephosphorylation of HSF1 (Ser(230)), and enhanced the translocation of HSF1 into cytosol. The accumulated HSF1 in cytosol led to downregulation of Hsp47 expression, resulting in the reduction of collagen production. Consistently, HSF1 silencing by siRNA prevented Hsp47 induction and subsequent collagen production, whereas overexpression of HSF1 restored the expression level of Hsp47 as well as collagen production in response to TRAIL treatment in LX-2 cells. Taken together, our data suggested that TRAIL induced HSF1 inactivation, consequently leading to the suppression of Hsp47-dependent collagen production in activated human hepatic stellate cells. Therefore, this study suggests that TRAIL may be an effective strategy for antifibrotic therapy in liver fibrosis.
热休克蛋白 47（Hsp47）是一种胶原特异性分子伴侣，其活性与肝纤维化有关。在这项研究中，我们发现 TRAIL 以剂量和时间依赖的方式抑制 Hsp47 的表达，随后导致激活的人肝星状细胞 LX-2 细胞中胶原产生减少。在 LX-2 细胞中过表达 Hsp47 可获得 TRAIL 诱导的胶原减少的抗性，相反，用 siRNA 抑制 Hsp47 可增强 TRAIL 处理导致的胶原产生减少。此外，我们发现 Hsp47 的表达受热休克因子（HSF）1 的转录控制，HSF1 在激活的人肝星状细胞 LX-2 细胞中高度位于核内。TRAIL 处理 LX-2 细胞可降低 HSF1 的活性三聚体形成，增加 HSF1 的去磷酸化（Ser（230）），并增强 HSF1 向细胞质的易位。细胞质中积累的 HSF1 导致 Hsp47 表达下调，从而减少胶原产生。一致地，用 siRNA 沉默 HSF1 可防止 Hsp47 诱导和随后的胶原产生，而 HSF1 的过表达可恢复 TRAIL 处理后 LX-2 细胞中 Hsp47 的表达水平以及胶原产生。总之，我们的数据表明，TRAIL 诱导 HSF1 失活，进而导致激活的人肝星状细胞中 Hsp47 依赖性胶原产生受到抑制。因此，本研究表明 TRAIL 可能是肝纤维化抗纤维化治疗的有效策略。
