Hepatitis C virus and HIV envelope proteins collaboratively mediate interleukin-8 secretion through activation of p38 MAP kinase and SHP2 in hepatocytes
Hepatitis C virus and HIV envelope proteins collaboratively mediate interleukin-8 secretion through activation of p38 MAP kinase and SHP2 in hepatocytes
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DOI：
10.1074/jbc.m302889200
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发表时间：
2003-09-12
影响因子：
4.8
通讯作者：
Groopman, JE
中科院分区：
文献类型：
--
作者：
Balasubramanian, A;Ganju, RK;Groopman, JE
丙型肝炎病毒（HCV）感染约占人类免疫缺陷病毒（HIV）感染者的40%，由此引起的肝功能障碍是合并感染患者死亡的主要原因。我们假设暴露于HCV和HIV蛋白的肝细胞可能通过“无辜旁观者”机制对损伤敏感。为了评估这一点，我们在模型HepG 2细胞中研究了包膜蛋白，HCV的E2和HIV的gp 120的影响。在与HCV-E2和HIV-gp 120共刺激后，我们观察到IL-8诱导的有效促炎反应。此外，我们的研究表明，HCV-E2和HIV-gp 120协同作用，触发一组特定的下游信号通路，包括激活p38丝裂原活化蛋白（MAP）激酶和酪氨酸磷酸酶，SHP 2。p38 MAP激酶的特异性抑制剂和有效的蛋白酪氨酸磷酸酶抑制剂钒酸钠均以剂量依赖性方式阻断IL-8的产生。p38 MAP激酶和SHP 2的作用通过瞬时过表达这些蛋白质的显性负突变体到HepG 2细胞中进一步确定。这些研究表明，过表达失活的p38 MAP激酶或SHP 2突变体部分废除了HCV-E2和HIV-gp 120诱导的IL-8产生。进一步的研究表明，IL-8诱导不是通过NF-κ B通路的激活介导的。然而，HCV-E2加HIV-gp 120显示增加AP-1的DNA结合活性。这些结果强调了由HCV-E2和HIV-gp 120诱导的促炎趋化因子IL-8的表达可能通过p38 MAP激酶和SHP 2以NF κ B非依赖性方式介导，尽管是通过AP-1驱动的过程。
Hepatitis C virus (HCV) infects similar to40% of human immunodeficiency virus (HIV) patients, and the resulting hepatic dysfunction that occurs is the primary cause of death in patients with co-infection. We hypothesized that hepatocytes exposed to HCV and HIV proteins might be susceptible to injury via an "innocent bystander" mechanism. To assess this, we studied the effects of envelope proteins, E2 of HCV and gp120 of HIV, in model HepG2 cells. Upon co-stimulation with HCV-E2 and HIV-gp120, we observed a potent proinflammatory response with the induction of IL-8. Furthermore, our studies revealed that HCV-E2 and HIV-gp120 act collaboratively to trigger a specific set of downstream signaling pathways that include activation of p38 mitogen-activated protein (MAP) kinase and the tyrosine phosphatase, SHP2. Both specific inhibitors of p38 MAP kinase and sodium vanadate, a potent protein-tyrosine phosphatase inhibitor, blocked IL-8 production in a dose-dependent manner. The role of p38 MAP kinase and SHP2 was further defined by transiently overexpressing dominant negative mutants of these proteins into HepG2 cells. These studies revealed that overexpression of an inactive p38 MAP kinase or SHP2 mutant partially abrogated HCV-E2- and HIV-gp120-induced IL-8 production. Further studies revealed that IL-8 induction was not mediated through activation of the NF-kappaB pathway. However, HCV-E2 plus HIV-gp120 was shown to increase the DNA binding activity of AP-1. These results emphasize that expression of the proinflammatory chemokine IL-8, induced by HCV-E2 and HIV-gp120, may be mediated through p38 MAP kinase and SHP2 in an NFkappaB- independent manner, albeit through AP-1-driven processes.