Increased intrahepatic cyclooxygenase 2, matrix metalloproteinase 2, and matrix metalloproteinase 9 expression is associated with progressive liver disease in chronic hepatitis C virus infection: role of viral core and NS5A proteins

Abstract

Background: Cyclooxygenase 2 (COX-2) and matrix metalloproteinases (MMPs) have been implicated in tissue injury and fibrogenesis in animal models but little is known regarding their role in hepatitis C virus (HCV) related liver disease in humans. Aims: To characterise the intrahepatic expression pattern of COX-2 and MMPs in chronic HCV infection and determine whether HCV core and NS5A proteins could promote their expression in cultured hepatocyte derived cell lines. Patients: Thirty two anti-HCV+ and 10 anti-HCV2 patients were studied. Methods: Western blot, reverse transcription-polymerase chain reaction (RT-PCR), enzyme immunoassay, and immunohistochemistry were used to assess the expression pattern of COX-2 and MMPs in liver biopsy samples from all patients. COX-2 gene expression and MMP-9 protein levels were also determined by immunoblot, RT-PCR, and luciferase assays in core and NS5A transfected hepatocyte derived cells. Results: The intrahepatic expression level of COX-2, MMP-2, and MMP-9 was significantly higher in HCV+ than in HCV2 patients, increasing with the fibrotic stage of liver disease. We further demonstrated that COX-2 mRNA, protein, and activity were induced in resting and activated core and NS5A transfectants. Both viral proteins induced transcriptional activity of the COX-2 gene promoter whereas core, but not NS5A, exerted an inducer effect on MMP-9 protein levels in cultured hepatocyte derived cells. Conclusions: Intrahepatic COX-2, MMP-2, and MMP-9 overexpression is associated with progressive hepatic fibrosis in chronic HCV infection, suggesting their pathogenic role in fibrogenesis. HCV core and NS5A proteins were able to upregulate COX-2 and MMP-9 gene expression in hepatocyte derived cells, providing a potential mechanism for hepatic fibrosis during chronic HCV infection.

Assessment of Cox2 and CMV in patients with chronic HCV infection

“…COX-2 is concerned in anti-apoptosis, inflammation and carcinogenesis. This result agreed with Nunez et al 24 was found COX-2 is over expressed in the liver tissue in patients with chronic HCV infection and that the COX-2 hepatic upregulation was present especially at areas of active inflammation. These results were explained by the major action of COX-2 as factor in inflammation with the final induction of COX-2 in necro-inflammatory injury of the liver 25 Bassiouny et al 26 reported that the up-regulation of COX-2 expression was apparent in patients with chronic HCV infection Regardless of the presence of cirrhosis while 80% of cirrhotic cases showed marked COX-2 expression.…”

“…11 High COX-2 expression has been reported to be relationship with liver damage and the liver cell pathologies such as the degree of inflammation, the viral infections, the development of fibrosis and HCC in human. 12,13 This was illustrated by the effect of COX-2 on the secretion of matrix metalloproteinases (MMPs) by liver cells that be implicated in carcinogenesis and fibrinogenesis occurring in HCV-induced liver disease.…”

Role of free radicals in liver diseases

“…HCV core gene expression diminishes the intracellular GSH levels and the mitochondrial NADPH content that are associated with increased uptake of calcium and oxidative stress generation at complex I in mitochondria, providing an action mechanism for HCVinduced ROS production [42,91,92,96]. On the contrary, core protein modulates the production of cytokines and host enzymes, such as cyclooxygenase-2 and inducible nitric oxide synthase (iNOS), which can increase ROS and RNS [97][98][99][100][101][102][103].…”

Protection against Fas-induced liver apoptosis in transgenic mice expressing cyclooxygenase 2 in hepatocytes

“…partial hepatectomy, 9,13 expression of COX-2 has been detected in animal models of cirrhosis, 14 after hepatitis B and C virus infection, 15,16 in human hepatoma cell lines, 17,18 in cholangiocarcinoma, 19 and in HCC. 20 Despite these observations, the question of whether COX-2 overexpression is sufficient to induce tumorigenesis has not been addressed.…”