Hepatitis C virus core protein suppresses NF-κB activation and cyclooxygenase-2 expression by direct interaction with IκB kinase β

In addition to hepatocytes, hepatitis C virus (HCV) infects immune cells, including macrophages. However, little is known concerning the impact of HCV infection on cellular functions of these immune effector cells. Lipopolysaccharide (LPS) activates I kappa beta kinase (IKK) signalsome and NF-kappa beta, which leads to the expression of cyclooxygenase-2 (COX-2), which catalyzes production of prostaglandins, potent effectors on inflammation and possibly hepatitis. Here, we examined whether expression of HCV core interferes with IKK signalsome activity and COX-2 expression in activated macrophages. In reporter assays, HCV core inhibited NF-kappa beta activation in RAW 264.7 and MH-S murine macrophage cell lines treated with bacterial LPS. HCV core inhibited IKK signalsome and IKK beta kinase activities induced by tumor necrosis factor alpha in HeLa cells and coexpressed IKK gamma in 293 cells, respectively. HCV core was coprecipitated with IKK beta and prevented nuclear translocation of IKK beta. NF-kappa beta activation by either LPS or overexpression of IKKP was sufficient to induce robust expression of COX-2, which was markedly suppressed by ectopic expression of HCV core. Together, these data indicate that HCV core suppresses IKK signalsome activity, which blunts COX-2 expression in macrophages. Additional studies are necessary to determine whether interrupted COX-2 expression by HCV core contributes to HCV pathogenesis.