MAP KINASE ACTIVATION IS INVOLVED IN POST- TRANSCRIPTIONAL REGULATION OF RSV-INDUCED RANTES GENE EXPRESSION Running title: Role of MAPK in RSV-induced RANTES expression

Airway epithelial cells represent the primary cell target of Respiratory Syncytial Virus (RSV) infection. They actively participate in the lung immune/inflammatory response that follows RSV infection by expressing chemokines, small chemotactic cytokines, which recruit and activate leukocytes. RANTES (Regulated upon Activation, Normal T cell Expressed and presumably Secreted) is a member of the CC chemokine subfamily and is strongly chemotactic for Tlymphocytes, monocytes, basophils and eosinophils, all cell types which are present or activated in the inflammatory infiltrate that follows RSV infection of the lung. RSV infection of airway epithelial cells induces RANTES expression by increasing gene transcription and stabilizing RNA transcripts. The signaling pathway regulating RANTES gene expression following RSV infection has not been determined. In this study we examined the role of extracellular signalregulated kinase (ERK) and p38, both members of the mitogen-activated protein (MAP) kinase family, in RSV-induced RANTES production. The results showed that RSV infection of alveolar epithelial cells induced increase phosphorylation and catalytic activity of ERK and the upstream kinases Raf-1 and MAP/ERK kinase (MEK). Induction of the MAP signaling cascade required a replication-competent virus. RSV infection of alveolar epithelial cells also induced activation of p38 MAP kinase. Inhibition of ERK and p38 activation significantly reduced RSVinduced RANTES mRNA and protein secretion, without affecting RANTES gene transcription or transcription factor activation. These results indicate that the MAP kinase signaling cascade regulates RANTES production in alveolar epithelial cells through a post-transcriptional mechanism.