INTERFERON (IFN)-ALPHA ACTIVATION OF HUMAN BLOOD MONONUCLEAR-CELLS IN-VITRO AND IN-VIVO FOR NITRIC-OXIDE SYNTHASE (NOS) TYPE-2 MESSENGER-RNA AND PROTEIN EXPRESSION - POSSIBLE RELATIONSHIP OF INDUCED NOS2 TO THE ANTI-HEPATITIS-C EFFECTS OF IFN-ALPHA IN-VIVO

Although researchers have noted high level activation of rodent mononu clear phagocytes for nitric oxide (NO) synthase type 2 (S2) expression and NO production with a variety of agents such as interferon (IFN) g amma and endotoxin, it has been difficult to demonstrate activation of human mononuclear phagocytes. The purpose of this study was to determ ine if IFN-alpha serves as an activator in vitro and in vivo in humans . Treatment of normal monocytes or mononuclear cells in vitro with IFN -alpha caused a dose-dependent increase in monocyte NOS2 activity and NO production, and increased expression of NOS2 protein and mRNA expre ssion. To determine if in vivo administration of IFN-alpha also modula ted NOS2, we studied blood cells from patients with hepatitis C before anc after IFN-alpha therapy. Untreated patients with chronic hepatiti s C virus infection had levels of NOS activity and NOS2 antigen in fre shly isolated mononuclear cells similar to those of healthy subjects, and they expressed minimal or no NOS2 mRNA. However, IFN-alpha treatme nt of patients with hepatitis C infection was associated with a signif icant elevation in mononuclear cell NOS activity, NOS2 antigen content , and NOS2 mRNA content. IFN-alpha-treated patients had significant de creases in levels of serum alanine aminotransferase and plasma hepatit is C mRNA. The degree of IFN-alpha-enhanced mononuclear cell NOS2 anti gen content correlated significantly with the degree of reduction in s erum alanine aminotransferase levels. Thus, IFN-alpha treatment of cel ls in vitro or administration of IFN-alpha to hepatitis C patients in vivo increases expression of mononuclear cell NOS2 mRNA reported to ha ve antiviral activity for variety of viruses, we speculate that induce d NO production may be related to the antiviral action(s) of IFN-alpha in hepatitis C infection.