Induction of RANTES/CCL5 by herpes simplex virus is regulated by nuclear factor kappa B and interferon regulatory factor 3.

Chemokines regulate migration of leukocytes to sites of infection. In this work, we have shown that the chemokine RANTES/CCL5 is produced after herpes simplex virus (HSV) infection of macrophages and fibroblasts and provide data on the underlying molecular mechanism. Reporter gene assays showed HSV-induced RANTES production to be regulated at the transcriptional level. Expression of RANTES was blocked by N-tosyl-L-phenylalanine, an inhibitor of the nuclear factor kappa B (NF-kappa B) pathway and also in cell lines stably expressing a dominant-negative mutant of I kappa B kinase beta. Cell lines stably expressing a dominant-negative mutant of interferon regulatory factor 3 (IRF-3) also produced dramatically decreased levels of RANTES after infection compared with the control cell line. In contrast, overexpression of dominant-negative p38 and also treatment with SB203580, an inhibitor of p38, did not significantly affect expression of RANTES. Taken together, these data suggest that HSV induces transcriptional activation of the RANTES gene through the transcription factors NF-kappa B and IRF-3.