It has been shown that oxidative stress occurs in chronic hepatitis C. Release of reactive oxygen species (ROS) from sequestered phagocytes and activated resident macrophages represents the predominant component of oxidative stress in the liver. However, little is known about the ability of the monocyte to produce ROS in response to protein of hepatitis C virus. In this study, we investigated the ROS production in human monocytes stimulated by several viral proteins of hepatitis C virus. Human monocytes from healthy blood donors were incubated with recombinant viral protein: Core, NS3, NS4, and NS5. ROS production was measured by chemiluminescence. Only NS3 triggered ROS production in human monocytes. Generated ROS were mainly the anion superoxide. NS3 also induced a rapid and transient increase in intracellular calcium concentration measured by a video digital microscopy technique. By using different metabolic inhibitors, we showed that ROS production requires calcium influx, tyrosine kinases, and the stress-activated protein kinase, p38. The study of p47 PHOX phosphorylation and translocation showed that NADPH oxidase was activated and involved in ROS production induced by NS3. In a second experiment, NS3 inhibited the oxidative burst induced by phorbol 12-myristate 13-acetate. These results indicate that NS3 activates NADPH oxidase and modulates ROS production, which may be involved in the natural history of hepatitis C infection.

Macrophage mannose receptor (MMR) is an important component of the innate immune system implicated in host defense against microbial infections such as candidiasis and in antigen presentation. We demonstrate here that the MMR expression is induced in mouse peritoneal macrophages following exposure to PPARgamma ligands or to interleukine-13 (IL-13) via a PPARgamma signaling pathway. Ligand activation of the PPARgamma in macrophages promotes uptake, killing of Candida albicans, and reactive oxygen intermediates production triggered by the yeasts through MMR overexpression. We also show that MMR induction by IL-13 via PPARgamma is dependent on phopholipase A2 activation and that IL-13 induces 15d-PGJ2 production and nuclear localization. These results reveal a novel signaling pathway controlling the MMR surface expression and suggest that endogenous PPARgamma ligand produced by phospholipase A2 activation may be an important regulator of MMR expression by IL-13.