Possible Involvement of Hepatitis B Virus Infection of Hepatocytes in the Attenuation of Apoptosis in Hepatic Stellate Cells.
Possible Involvement of Hepatitis B Virus Infection of Hepatocytes in the Attenuation of Apoptosis in Hepatic Stellate Cells.
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DOI：
10.1371/journal.pone.0146314
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Yokosuka O
中科院分区：
文献类型：
--
作者：
Sasaki R;Kanda T;Nakamura M;Nakamoto S;Haga Y;Wu S;Shirasawa H;Yokosuka O
诱导肝星状细胞(HSCs)凋亡是一种很有前途的治疗乙肝病毒(HBV)相关性肝纤维化的策略。然而，在考虑到乙肝病毒感染的情况下，肝星状细胞凋亡的潜在机制尚不清楚。本研究探讨了乙肝病毒对肝星状细胞凋亡和内质网应激信号的影响。研究了HepG2.2.15的条件培养液(CM)对蛋白酶体抑制剂MG132诱导的LX-2和HHSteC细胞c-jun凋亡的影响。C-jun与c-Fos结合形成AP-1早期反应转录因子，导致AP-1活化、信号转导、内质网应激和细胞凋亡。在LX-2细胞中，MG132处理与c-jun的磷酸化、AP-1的激活和细胞凋亡有关。然而，在来自HepG2.2.15的CM的存在下，这些现象被减弱。在HHSteC细胞中，也观察到了类似的结果。HBVDNA不参与HSC的凋亡过程。HBeAg可能对MG132诱导的LX-2细胞凋亡有抑制作用。我们还观察到几个内质网应激相关基因，如cAMP反应元件结合蛋白3样蛋白3、抑制素βA和溶质载体家族17成员2，在来自HepG2.2.15的CM或来自感染乙肝病毒的PXB细胞的CM的存在下上调。乙肝病毒抑制HSC中c-jun/AP-1的活化，有助于抑制细胞凋亡，导致肝纤维化。乙肝病毒还上调了几个与细胞生长和纤维化相关的内质网应激基因。这些机械性的见解可能会为治疗乙肝病毒相关性肝纤维化提供新的思路。
The induction of apoptosis in hepatic stellate cells (HSCs) is a promising therapeutic strategy against hepatitis B virus (HBV)-related hepatic fibrosis. The underlying mechanisms of apoptosis in HSCs, however, are unknown under consideration of HBV infection. In this study, the effects of HBV on apoptosis and endoplasmic reticulum (ER) stress signaling in HSCs were examined. The effects of conditioned media (CM) from HepG2.2.15 on apoptosis induced by the proteasome inhibitor MG132 in LX-2 and HHSteC were studied in regard to c-Jun. In combination with c-Fos, c-Jun forms the AP-1 early response transcription factor, leading to AP-1 activation, signal transduction, endoplasmic reticulum (ER) stress and apoptosis. In LX-2 cells, MG132 treatment was associated with the phosphorylation of c-Jun, activation of AP-1 and apoptosis. However, in the presence of CM from HepG2.2.15, these phenomena were attenuated. In HHSteC cells, similar results were observed. HBV genomic DNA is not involved in the process of HSC apoptosis. It is possible that HBeAg has an inhibitory effect on MG132-induced apoptosis in LX-2. We also observed the upregulation of several ER stress-associated genes, such as cAMP responsive element binding protein 3-like 3, inhibin-beta A and solute carrier family 17-member 2, in the presence of CM from HepG2.2.15, or CM from PXB cells infected with HBV. HBV inhibits the activation of c-Jun/AP-1 in HSCs, contributing to the attenuation of apoptosis and resulting in hepatic fibrosis. HBV also up-regulated several ER stress genes associated with cell growth and fibrosis. These mechanistic insights might shed new light on a treatment strategy for HBV-associated hepatic fibrosis.