Involvement of oxidative stress, NF-IL-6, and RANTES expression in dengue-2-virus-infected human liver cells

The liver has been suspected to be one of the major targets of dengue virus infection, Here, we detected increasing secretion of the chemokine RANTES (regulated upon activation, normal T cell expressed and secreted), which fu nctions to recruit the immune cells, in dengue-virus-infected liver cells a nd patients. Three luciferase reporter genes with various deletions at the 5'-end of the RANTES promoter were constructed to explore the RANTES activa tion mechanism in human liver cells. The reporter gene was optimally activa ted by dengue-2 virus when the RANTES promoter contains the region from the transcription starting site (+1) to the nucleotide at the -181 position. N F-IL-6 and an undefined factor forming DNA-protein complexes in the RANTES promoter E and A/B regions in the infected cells were demonstrated by elect rophoretic mobility shift assay. Further analysis showed that oxidative str ess was an upstream inducer of NF-IL-6 and RANTES signaling in dengue-virus -infected liver cells. This finding was demonstrated by three antioxidants (N-acetyl-L-cysteine, nitro-L-arginine methyl ester, and pyrrolidine dithio carbamate) used to suppress the activation. In contrast, the DNA binding ac tivity of the undefined factor was not affected by the antioxidant treatmen t, indicating the existence of an oxidant-independent pathway. We hypothesi ze that dengue virus infection of the liver cells may trigger both an oxida nt-dependent and an oxidant-independent pathway to up-regulate RANTES mRNA expression through activating NF-IL-6 and an undefined factor, respectively . In conclusion, the present study suggests a new direction for the study o f liver pathogenesis involving RANTES in host immune responses during dengu e Virus infection. (C) 2000 Academic Press.