scholarly journals Hepatitis C Virus Stimulates the Expression of Cyclooxygenase-2 via Oxidative Stress: Role of Prostaglandin E2 in RNA Replication

2005 ◽  
Vol 79 (15) ◽  
pp. 9725-9734 ◽  
Author(s):  
Gulam Waris ◽  
Aleem Siddiqui
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Glycogen Synthase ◽  
Rna Replication ◽  
Cyclooxygenase 2 ◽  
Prostaglandin E ◽  
Pyrrolidine Dithiocarbamate ◽  
Cox 2

ABSTRACT Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, which can lead to the development of liver cirrhosis and hepatocellular carcinoma. Recently, the activation of cyclooxygenase-2 (Cox-2) has been implicated in the HCV-associated hepatocellular carcinoma. In this study, we focus on the signaling pathway leading to Cox-2 activation induced by HCV gene expression. Here, we demonstrate that the HCV-induced reactive oxygen species and subsequent activation of NF-κB mediate the activation of Cox-2. The HCV-induced Cox-2 was sensitive to antioxidant (pyrrolidine dithiocarbamate), Ca2+ chelator (BAPTA-AM), and calpain inhibitor (N-acetyl-Leu-Leu-Met-H). The levels of prostaglandin E2 (PGE2), the product of Cox-2 activity, are increased in HCV-expressing cells. Furthermore, HCV-expressing cells treated with the inhibitors of Cox-2 (celecoxib and NS-398) showed significant reduction in PGE2 levels. We also observed the enhanced phosphorylation of Akt and its downstream substrates glycogen synthase kinase-3β and proapoptotic Bad in the HCV replicon-expressing cells. These phosphorylation events were sensitive to inhibitors of Cox-2 (celecoxib and NS-398) and phosphatidylinositol 3-kinase (LY294002). Our results also suggest a potential role of Cox-2 and PGE2 in HCV RNA replication. These studies provide insight into the mechanisms by which HCV induces intracellular events relevant to liver pathogenesis associated with viral infection.

scholarly journals Hepatitis C Virus Core Protein Suppresses NF-κB Activation and Cyclooxygenase-2 Expression by Direct Interaction with IκB Kinase β

2005 ◽  
Vol 79 (12) ◽  
pp. 7648-7657 ◽  
Author(s):  
Myungsoo Joo ◽  
Young S. Hahn ◽  
Minjae Kwon ◽  
Ruxana T. Sadikot ◽  
Timothy S. Blackwell ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Nuclear Translocation ◽  
Core Protein ◽  
Ectopic Expression ◽  
Cyclooxygenase 2 ◽  
Necrosis Factor Alpha ◽  
Iκb Kinase ◽  
Cox 2 ◽  
The Impact

ABSTRACT In addition to hepatocytes, hepatitis C virus (HCV) infects immune cells, including macrophages. However, little is known concerning the impact of HCV infection on cellular functions of these immune effector cells. Lipopolysaccharide (LPS) activates IκB kinase (IKK) signalsome and NF-κB, which leads to the expression of cyclooxygenase-2 (COX-2), which catalyzes production of prostaglandins, potent effectors on inflammation and possibly hepatitis. Here, we examined whether expression of HCV core interferes with IKK signalsome activity and COX-2 expression in activated macrophages. In reporter assays, HCV core inhibited NF-κB activation in RAW 264.7 and MH-S murine macrophage cell lines treated with bacterial LPS. HCV core inhibited IKK signalsome and IKKβ kinase activities induced by tumor necrosis factor alpha in HeLa cells and coexpressed IKKγ in 293 cells, respectively. HCV core was coprecipitated with IΚΚβ and prevented nuclear translocation of IKKβ. NF-κB activation by either LPS or overexpression of IKKβ was sufficient to induce robust expression of COX-2, which was markedly suppressed by ectopic expression of HCV core. Together, these data indicate that HCV core suppresses IKK signalsome activity, which blunts COX-2 expression in macrophages. Additional studies are necessary to determine whether interrupted COX-2 expression by HCV core contributes to HCV pathogenesis.

Role of Myeloperoxidase in hepatitis C virus related hepatocellular carcinoma

Meta Gene ◽  
2018 ◽  
Vol 18 ◽  
pp. 1-8 ◽  
Author(s):  
Mohamed Abdel-Hamid ◽  
Ola Hassan Nada ◽  
Doha El-Sayed Ellakwa ◽  
Lamiaa Khalaf Ahmed
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepatitis C Virus ◽  
Hepatitis C

The role of cyclins and cyclin dependent kinases in development and progression of hepatitis C virus-genotype 4-associated hepatitis and hepatocellular carcinoma

2011 ◽  
Vol 91 (2) ◽  
pp. 643-652 ◽  
Author(s):  
Abeer A. Bahnassy ◽  
Abdel-Rahman N. Zekri ◽  
Samah A. Loutfy ◽  
Waleed S. Mohamed ◽  
Amrallah Abdel Moneim ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virus Genotype ◽  
Genotype 4 ◽  
Cyclin Dependent Kinases

scholarly journals Hepatitis C Virus (HCV) Constitutively Activates STAT-3 via Oxidative Stress: Role of STAT-3 in HCV Replication

2005 ◽  
Vol 79 (3) ◽  
pp. 1569-1580 ◽  
Author(s):  
Gulam Waris ◽  
James Turkson ◽  
Tarek Hassanein ◽  
Aleem Siddiqui
Keyword(s):  
Oxidative Stress ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Hcv Rna ◽  
Pyrrolidine Dithiocarbamate ◽  
Constitutive Activation ◽  
Mitogen Activated Protein

ABSTRACT The hepatitis C virus (HCV) causes chronic hepatitis, which often results in liver cirrhosis and hepatocellular carcinoma. We have previously shown that HCV nonstructural proteins induce activation of STAT-3 via oxidative stress and Ca2+ signaling (G. Gong, G. Waris, R. Tanveer, and A. Siddiqui, Proc. Natl. Acad. Sci. USA 98:9599-9604, 2001). In this study, we focus on the signaling pathway leading to STAT-3 activation in response to oxidative stress induced by HCV translation and replication activities. Here, we demonstrate the constitutive activation of STAT-3 in HCV replicon-expressing cells. The HCV-induced STAT-3 activation was inhibited in the presence of antioxidant (pyrrolidine dithiocarbamate) and Ca2+ chelators (BAPTA-AM and TMB-8). Previous studies have shown that maximum STAT-3 transactivation requires Ser727 phosphorylation in addition to tyrosine phosphorylation. Using a series of inhibitors and dominant negative mutants, we show that HCV-induced activation of STAT-3 is mediated by oxidative stress and influenced by the activation of cellular kinases, including p38 mitogen-activated protein kinase, JNK, JAK-2, and Src. Our results also suggest a potential role of STAT-3 in HCV RNA replication. We also observed the constitutive activation of STAT-3 in the liver biopsy of an HCV-infected patient. These studies provide an insight into the mechanisms by which HCV induces intracellular events relevant to liver pathogenesis associated with the viral infection.

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