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Inhibition of IκB kinase by thalidomide increases hepatitis C virus RNA replication
Author(s) -
Rance E.,
Tanner J. E.,
Alfieri C.
Publication year - 2012
Publication title -
journal of viral hepatitis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.329
H-Index - 100
eISSN - 1365-2893
pISSN - 1352-0504
DOI - 10.1111/j.1365-2893.2011.01505.x
Subject(s) - virology , replication (statistics) , viral replication , hepatitis c virus , rna , thalidomide , hepatitis b virus , biology , medicine , virus , genetics , immunology , gene , multiple myeloma
Summary. 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 μ m ). 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.