HCV NS5A Up-Regulates COX-2 Expression via IL-8-Mediated Activation of the ERK/JNK MAPK Pathway

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.

Grape Seed Extract Attenuates Hepatitis C Virus Replication and Virus-Induced Inflammation

“…The aberrant expression of COX-2 observed in chronic hepatitis C patients was associated with an increased risk of HCC (Bae et al, 2001). As mentioned earlier, the HCV protein greatly stimulated COX-2 expression and in turn, COX-2 overexpression enhanced HCV replication (Chen et al, 2015). Because of these observations, our previous studies have proved that several natural products can effectively suppress HCV replication by inhibiting NF-kB-mediated COX-2 expression, which supported targeting the COX-2 signaling pathway as a promising approach to develop therapeutic or chemopreventive agents against HCV-positive HCC formation (Lee et al, 2011; Lin et al, 2013).…”

“…In Trujillo-Murillo et al (2007) study, the HCV genomic RNA and COX-2 were co-transfected in Huh-7 cell and the viral RNA replication were elevated with COX-2 induction in concentration-dependent manner. Besides, we recently showed that suppression of COX-2 could be a useful approach for development of HCV inhibitors (Chen et al, 2015; Lin et al, 2015). Furthermore, COX-2 metabolite PEGs is a risk factor to develop HCC (Loginov and Vysotskaia, 1995).…”

“…Cyclooxygenase-2 is an important pro-inflammatory mediator that responses to diverse inflammatory stimuli such as a 12- O -tetradecanoylphorbol-13-acetate (TPA) treatment or a virus infection (Kim et al, 2010; Radi et al, 2010; Chen et al, 2015). The prostaglandins converted from arachidonic acid by COX-2 have been reported to enhance tumor growth and angiogenesis in various tumors (Chang et al, 2004; Tveteraas et al, 2012).…”

Porcine reproductive and respiratory syndrome virus (PRRSV) up-regulates IL-8 expression through TAK-1/JNK/AP-1 pathways

“…Moreover, our results suggest that JNK pathway is more essential for PRRSV induced IL-8 expression as JNK and c-Jun inhibitor and siRNA knockdown of c-Jun and c-Fos significantly reduced IL-8 expression. Similarly, under stimulation of HIV-1, HCV and Papillomavirus, the expression of IL-8 is also JNK dependent (Chen et al, 2015;Gangwani and Kumar, 2015;Saeed et al, 2015;Zhang et al, 2014). JNK isoforms are strongly activated in response to various cellular stresses (Cargnello and Roux, 2011).…”

Host Innate Immunity against Hepatitis E Virus and Viral Evasion Mechanisms

“…Other cytokines, such as IFN-β and IFN-γ, displayed an antagonistic effect on the expression of IL-8 [75][76][77]. Analogously, HCV-encoded E2 and NS5A inhibited expression of IFN-β and downstream ISGs through upregulation of IL-8 [78][79][80]. In addition, as shown in HEV infection, AP-1 was required for IFN-β gene transcription as it binds to the PRD IV element of the IFN-β promoter, inducing assembly of IFN-β enhanceosome [81].…”