TRANSCRIPTIONAL INDUCTION OF MULTIPLE CYTOKINES BY HUMAN RESPIRATORY SYNCYTIAL VIRUS REQUIRES ACTIVATION OF NF-KAPPA-B AND IS INHIBITED BY SODIUM-SALICYLATE AND ASPIRIN

infection of the lung epithelial cell line A549 by respiratory syncyti al virus (RSV) resulted in the elevated synthesis of multiple cellular cytokines, including a number of interleukins (ILs). Detailed studies of IL-11 induction revealed that it required infection by viable viru s and involved a net increase in the steady state level of IL-11 mRNA. Nuclear run-on assays showed a direct effect of RSV on IL-11 gene tra nscription. Mutational analysis of the IL-11 promoter fused to a repor ter luciferase gene demonstrated the requirement of a region 720 nucle otides upstream of the mRNA start site in the transcriptional inductio n of IL-11 by RSV. Two nearly identical 10-nucleotide-long sequences G GGGTCTCCC and GGGTCTCCCC in this region resembled the NF-kappa B conse nsus motif. Mutation of either sequence greatly reduced RSV-mediated i nduction of IL-11 promoter activity. NF-kappa B sites in IL-1 alpha, I L-6, and IL-8 promoters were also required for RSV-mediated induction of transcription of these promoters. Immunological studies and use of reporter gene constructs provided direct evidence for the activation a nd nuclear translocation of NF-kappa B by RSV. Sodium salicylate and a spirin, inhibitors of NF-kappa B activation, abolished transcriptional induction of all these cytokines by RSV. Together, these studies demo nstrated an essential role of NF-kappa B in RSV-mediated transcription of multiple cytokines genes and suggested a possible use of salicylat es in managing airway inflammation and viral pathogenesis during RSV i nfection. (C) 1997 Academic Press.