Abstract
Chronic hepatitis C virus (HCV) infection leads to intrahepatic inflammation and liver cell injury, which are considered a risk factor for virus-associated hepatitis, cirrhosis, and hepatocellular carcinoma worldwide. Inflammatory cytokines are critical components of the immune system and influence cellular signaling, and genetic imbalances. In this study, we found that cyclooxygenase-2 (COX-2) and interleukin-8 (IL-8) were significantly induced by HCV infection and HCV NS5A expression, and induction of COX-2 correlated with HCV-induced IL-8 production. We also found that the ERK and JNK signaling pathways were involved in the regulation of IL-8-mediated COX-2 induction in response to HCV infection. Using a promoter-linked reporter assay, we identified that the C/EBP regulatory element within the COX-2 promoter was the dominant factor responsible for the induction of COX-2 by HCV. Silencing C/EBP attenuated HCV-induced COX-2 expression. Our results revealed that HCV-induced inflammation promotes viral replication, providing new insights into the involvement of IL-8-mediated COX-2 induction in HCV replication.
Highlights
The hepatitis C virus (HCV) is a hepatotropic, non-cytopathic virus that can cause hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) [1]
We demonstrated that HCV infection and HCV NS5A overexpression up-regulate COX-2 expression
We demonstrated that HCV infection induced COX-2 expression through MAPK pathway (ERK and JNK) activation with viral-induced IL-8
Summary
The hepatitis C virus (HCV) is a hepatotropic, non-cytopathic virus that can cause hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) [1]. HCV core, NS3, and N5A proteins have been reported to result in cytokine imbalance and stimulation of cell growth or suppression of apoptosis for promoting HCC development [5, 6]. Increased levels of COX-2 and prostaglandins (PGs) contribute to various biological processes, including acute and chronic inflammation, oxidative stress, bacterial and viral infection, and cancer [10, 11]. Previous reports demonstrated that the expression of COX-2 was stimulated in response to HCV infection [12, 13]. We found that the induction of COX-2 was mediated by HCV-induced IL-8 production In this context, the transcription factor C/EBP and the ERK/ JNK signaling pathway were investigated to determine their roles in the regulation of IL8-mediated COX-2 expression by HCV
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