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J. Biol. Chem., Vol. 278, Issue 37, 35755-35766, September 12, 2003

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Hepatitis C Virus and HIV Envelope Proteins Collaboratively Mediate Interleukin-8 Secretion through Activation of p38 MAP Kinase and SHP2 in Hepatocytes^*

Anuradha Balasubramanian, Ramesh K. Ganju   and Jerome E. Groopman  ¶

From the Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, Massachusetts 02115

Hepatitis C virus (HCV) infects 40% 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-B 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 NF-B-independent manner, albeit through AP-1-driven processes.

Received for publication, March 20, 2003 , and in revised form, June 17, 2003.

^* This work was supported in part by National Institutes of Health Grants DA15008 (to J. E. G.) and AI49140 (to R. K. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors share senior authorship.

To whom correspondence may be addressed: HIM/BIDMC, Rm. 343, 4 Blackfan Circle, Boston, MA 02115. E-mail: rganju{at}bidmc.harvard.edu.

^¶ To whom correspondence may be addressed: HIM/BIDMC, Rm. 342, 4 Blackfan Circle, Boston, MA 02115. E-mail: jgroopma{at}bidmc.harvard.edu.

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