clusters. [3][4][5][6] Recently, the degree of hepatic inflammatory ac-Hepatitis C virus (HCV) causes acute and often also chronic tivity has been shown to be positively correlated to the exliver disease. Hepatocellular injury might result from both a pression of interferon-gamma (IFN-g) transcripts within host response directed to inhibit viral spread and from proliver tissue from HCV-infected individuals. 7 This finding has cesses initiated by the virus itself. To study mechanisms inbeen particularly in line with several models of experimenvolved in hepatocellular injury, liver tissue from chronically tally induced hepatitis, all of them pointing to a role of IFN-HCV-infected patients was analyzed for the expression of the g as a mediator of the hepatic inflammatory process. 8-12 inducible isoform of nitric oxide synthase (iNOS) and for
In addition to its proinflammatory activity, in some experiinterferon gamma (IFN-g) by a quantitative, competitive remental systems, IFN-g is known to exert antiviral effects as verse-transcription-polymerase chain reaction (RT-PCR) technique. Moreover, hepatic viral load was determined by well. [13][14][15] However, not least because of the lack of a suitable two independent techniques, and liver tissue was evaluated cell culture system for HCV propagation, nothing is known histopathologically in detail. Liver tissue from HCV-infected about antiviral effects of IFN-g on HCV replication at present.
patients was shown to express elevated levels of iNOS tran-
Recent experiments with IFN-g neutralizing antibodies and scripts compared with non-HCV-infected patients. Increased with IFN-g and IFN-g receptor gene-targeted mice infected iNOS transcript expression, however, was not accompanied with influenza virus, 16,17 vaccinia virus, or lymphocytic chorioby significantly elevated serum nitrite plus nitrate (NOx) conmeningitis virus 18 revealed that IFN-g exerts its antiviral activcentration, although some of the chronic HCV-infected paity, at least in these systems, not on the level of a virus-specific tients reached markedly higher serum NOx levels than the cytotoxic T-lymphocyte response. In contrast, the antiviral control group or healthy individuals, respectively. Hepatic activity of IFN-g has rather been shown to be related to the iNOS expression was found to be positively correlated to capacity of macrophages to produce nitric oxide (NO). 18,19 hepatic HCV-RNA content on the one hand, and weakly to
The highly reactive radical NO is derived from L-arginine hepatic IFN-g expression, previously shown to be solely assoby oxidation of the guanidino nitrogen catalyzed by NO synciated with hepatic necro-inflammatory activity among the thase. 20 Two distinct NO synthase isoforms are constitutively histopathological parameters studied, on the other hand. In expressed at basal levels primarily in neuronal and endothecontrast to IFN-g transcript expression, neither hepatic iNOS lial cells. A third, inducible isoform (iNOS) is expressed in expression nor hepatic HCV-RNA content were related to macrophages and hepatocytes and produces high amounts hepatic inflammatory activity. The presented data are compatof NO in response to cytokines, e.g., IFN-g, or lipopolysacible with the assumption that HCV might be able to stimulate charide (LPS). Whereas constitutive NO synthase activity iNOS expression both directly and indirectly via its capacity maintains normal physiology, the microbicidal, tumoricidal, to induce IFN-g. (HEPATOLOGY 1997;26:451-458.) inflammatory, and the above-mentioned antiviral effects of NO are ascribed to the activity of the inducible isoform. The Hepatitis C virus (HCV) infection causes acute and often effector mechanisms of NO might be many and diverse. For also chronic liver disease. 1,2 Histopathologically, a mostly instance, its tumoricidal effect might be because of inhibition mild inflammatory activity might be accompanied by of ribonucleotide reductase, the rate-limiting enzyme in DNA steatosis, fibrosis, bile duct lesions, or intraportal lymphoid synthesis. Another important mechanism, by which NO might affect pathogens, is thought to be the inactivation of Abbreviations: HCV, hepatitis C virus; IFN-g, interferon gamma; NO, nitric oxide; enzymes requiring iron and sulfur prosthetic groups for their iNOS, inducible isoform; LPS, lipopolysaccharide; ALT, alanine transaminase; RTcatalytic activity by forming nitrosyl-iron-sulfur complexes. 20 PCR, reverse-transcription polymerase chain reaction; mRNA, messenger RNA; cDNA, In the context of the previously shown elevated levels of complementary DNA; NOx, nitrite plus nitrate; NF-kB, nuclear transcription factor kB; TBE-V, tick-borne encephalitis virus.
IFN-g transcripts in liver tissue from patients with chronic
From the Division of Gastroenterology and Endocrinology,