Nonstructural 3 Protein of Hepatitis C Virus Triggers an Oxidative Burst in Human Monocytes via Activation of NADPH Oxidase

Abstract

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.

Redox modulation of the hepatitis C virus replication complex is calcium dependent

“…4). The data suggest that endogenous generation of oxidants, either due to normal cell metabolism or triggered by HCV proteins expression [15,16,[18][19][20][21], might be sufficient to modulate HCV RC in these cells. Most of all, however, the data indicate that ROS might suppress HCV RC while antioxidants, favor HCV RNA replication by antagonizing the suppressive effects of oxidants.…”

“…Although these findings are difficult to reconcile, some of the discrepancies may be explained by the effects that some HCV proteins have on the host redox status [15][16][17][18][19][20][21]. It is also possible that antioxidants have other effects, such as on the immune system, which leads to an overall …”

“…HCV infection is associated with increases in various markers of oxidative stress in patients [10][11][12][13]. In addition to chronic inflammation, iron overload and some of HCV proteins may help increase the oxidative burden [10,[14][15][16][17][18][19][20][21].…”

Reactive oxygen signaling and MAPK activation distinguish Epstein–Barr Virus (EBV)-positive versus EBV-negative Burkitt's lymphoma

“…Like EBV, cancers caused by hepatitis B, C, and human T cell lymphotropic virus have a high frequency of p16ink4a hypermethylation (40,41). Also, viral structural proteins, such as HBX of hepatitis B, HCV NS3, NS5, and human T cell lymphotropic virus tax protein, are known to induce reactive oxygen (42)(43)(44)(45). Reactive oxygen may play a decisive role in carcinogenesis in potentially most virally induced human cancers, and it may serve as a pharmacologic target for chemoprevention and treatment.…”

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

“…This RNA virus does not integrate into the host genome but likely induces HCC through viral proteins by host-protein interactions or via the proinflammatory response to the virus [14]. Several HCV proteins, including core, NS3, and NS5A, have been shown to induce oxidative stress in cultured cells [24,25]. ROS, which act as second messengers, activate cellular kinases, although the mechanism of this activation remains unclear.…”