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Hepatitis C is a devastating disease worldwide. Proteins encoded by the etiologic agent, hepatitis C virus (HCV), are believed to play important roles in HCV-associated pathogenesis. However, the biological functions of the non-structural protein-2 (NS2) encoded by HCV are not well characterized. Here, we show that HCV NS2 protein activates CXCL-8 (interleukin-8, IL-8) transcription in HepG2 cells as measured by reverse transcription-polymerase chain reaction and IL-8 promoter-luciferase reporter assays. Furthermore, when the κB site on the IL-8 promoter was eliminated by mutagenesis or when intracellular NF-κB activity was suppressed by an inhibitor, NS2 did not activate the IL-8 promoter, suggesting a role of NF-κB in this process. These results prompted us to hypothesize that HCV NS2 might be able to activate NF-κB. This hypothesis was tested by determination of NF-κB-driven reporter gene expression and NF-κB p65 subunit subcellular localization after HCV NS2 expression. Indeed, NS2 could up-regulate NF-κB-driven luciferase activity and was associated with p65 nuclear localization. These results demonstrate that HCV NS2 up-regulates IL-8 transcription through NF-κB. This newly identified function increases our understanding of the role of HCV NS2 protein in virus-host interactions. [ABSTRACT FROM AUTHOR]