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J. Biol. Chem., Vol. 280, Issue 12, 11329-11339, March 25, 2005

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Binding of Hepatitis C Virus Envelope Protein E2 to CD81 Up-regulates Matrix Metalloproteinase-2 in Human Hepatic Stellate Cells^*

Antonio Mazzocca, Silvia Cappadona Sciammetta, Vinicio Carloni, Lorenzo Cosmi, Francesco Annunziato, Takashi Harada¶, Sergio Abrignani¶, and Massimo Pinzani

From the Dipartimento di Medicina Interna, Centro di Ricerca, Trasferimento e Alta Formazione MCIDNENT Università di Firenze, I-50134 Firenze, Italy, and ^¶Chiron Vaccines Research Center, 53100 Siena, Italy

The hepatitis C virus (HCV) envelope E2 glycoprotein is a key molecule regulating the interaction of HCV with cell surface proteins. E2 binds the major extracellular loop of human CD81, a tetraspanin expressed on various cell types including hepatocytes and B lymphocytes. Regardless, information on the biological functions originating from this interaction are largely unknown. Since human hepatic stellate cells (HSC) express high levels of CD81 at the cell surface, we investigated the E2/CD81 interaction in human HSC and the possible effects arising from this interaction. Matrix metalloproteinase-2 (MMP-2; gelatinase A), a major enzyme involved in the degradation of normal hepatic extracellular matrix, was up-regulated following the interaction between E2 and CD81. In particular, by employing zymography and Western blot, we observed that E2 binding to CD81 induces a time-dependent increase in the synthesis and activity of MMP-2. This effect was abolished by preincubating HSC with an anti-CD81 neutralizing antibody. Similar effects were detected in NIH3T3 mouse fibroblasts transfected with human CD81 with identical time course features. In addition, E2/CD81 interaction in human HSC induced the up-regulation of MMP-2 by increasing activator protein-2/DNA binding activity via ERK/MAPK phosphorylation. Finally, suppression of CD81 by RNA interference in human HSC abolished the described effects of E2 on these cells, indicating that CD81 is essential for the activation of the signaling pathway leading to the up-regulation of MMP-2. These results suggest that HSC may represent a potential target for HCV. The interaction of HCV envelope with CD81 on the surface of human HSC induces an increased expression of MMP-2. Increased degradation of the normal hepatic extracellular matrix in areas where HCV is concentrated may favor inflammatory infiltration and further parenchymal damage.

Received for publication, September 3, 2004 , and in revised form, December 8, 2004.

^* This work was supported by grants from the Italian MURST (project "Cellular and Molecular Biology of Hepatic Fibrogenesis"), from the University of Florence, and from Banco di Roma (Rome, Italy). Financial support was also provided by the Italian Liver Foundation. 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.

To whom correspondence should be addressed: Dipartimento di Medicina Interna, Università di Firenze, 85 Viale Morgagni, Firenze I-50134, Italy. Tel.: 39-55-4296486; Fax: 39-55-417123; E-mail: a.mazzocca{at}dmi.unifi.it.

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