title: Inhibition of IκB kinase by thalidomide increases hepatitis C virus RNA replication.
abstract: Hepatic fibrosis is an integral element in the progression of chronic liver disease. Elevated hepatic interleukin (IL)-8 is an important contributor to fibrosis in patients chronically infected with the hepatitis C virus (HCV). Thalidomide has been used to reduce liver inflammation and fibrosis in HCV-infected patients, but its impact on HCV replication remains unclear. This study examined the effect of thalidomide on HCV replication in vitro. Results revealed that while thalidomide reduced IL-8 and nuclear factor kappa B (NF-κB) activity by 95% and 46% in Huh-7 cells, increasing concentrations of thalidomide correlated with a linear rise in HCV replication (17-fold at 200 μm). The NF-κB inhibitors, wedelolactone and NF-κB activation inhibitor-1, which mimic the actions of thalidomide by preventing phosphorylation and activation of IκB kinase (IKK) and hence block NF-κB activity, increased HCV RNA by 18- and 19-fold, respectively. During in vitro HCV replication in Huh-7 cells, we observed a 30% increase in IKKα protein and 55% decrease in NF-κB(p65)/RelA protein relative to cellular β-actin. Ectopic expression of IKKα to enhance the inactive form of IKK in cells undergoing virus replication led to a 13-fold increase in HCV RNA. Conversely, enhanced expression of NF-κB(p65)/RelA in infected cells resulted in a 17-fold reduction in HCV RNA. In conclusion, HCV RNA replication was significantly augmented by the inhibition of IKK activation and subsequent NF-κB signalling, whereas a restoration of NF-κB activity by the addition of NF-κB/RelA markedly reduced HCV replication. This study lends added importance to the role of the NF-κB signalling pathway in controlling HCV replication.
authors.affiliation: Laboratory of Viral Pathogenesis, Research Center, Sainte-Justine University Hospital, Montreal, QC, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Rance
authors.forename: J E
authors.initials: JE
authors.lastname: Tanner
authors.forename: C
authors.initials: C
authors.lastname: Alfieri
mesh_terms: D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016174:Hepacivirus / Q000254:growth & development*; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology / Q000821:virology; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D016209:Interleukin-8 / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D012367:RNA, Viral / Q000096:biosynthesis / Q000235:genetics; D013792:Thalidomide / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D016209:Interleukin-8; D016328:NF-kappa B; D012367:RNA, Viral; D013792:Thalidomide; D051550:I-kappa B Kinase