RANTES (regulated on activation normal T cell expressed and secreted) (> or =10 ng/ml) stimulates the induction of KC and other chemokines in astrocytes. Elements of the signal transduction pathway controlling this response were identified. RANTES induced phosphorylation of MEK, ERK1/2, p90 ribosomal S6 kinases (RSK), and cAMP-response element-binding protein (CREB) in astrocytes. U0126, a pharmacological inhibitor of MEK, blocked the phosphorylation of the downstream elements ERK, RSK, and CREB, inhibited chemokine synthesis, and reduced transcription from a KC promoter construct. Dominant negative mutants of RSK or CREB blocked the transcription driven by the KC promoter. Finally, RANTES treatment induces nuclear translocation of phosphorylated RSK in astrocytes. This novel role for RSK in signaling chemokine responses and synthesis in astrocytes may contribute to the amplification mechanisms responsible for prolonging inflammatory responses in the central nervous system.