Salicylic acid and aspirin inhibit the activity of RSK2 kinase and repressRSK2-dependent transcription of cyclic AMP response element binding protein- and NF-kappa B-responsive genes

Sodium salicylate (NaSal) and other nonsteroidal anti-inflammatory drugs (N SAIDs) coordinately inhibit the activity of NF-kappa B, activate heat shock transcription factor 1 and suppress cytokine gene expression in activated monocytes and macrophages, Because our preliminary studies indicated that t hese effects could be mimicked by inhibitors of signal transduction, we hav e studied the effects of NSAIDs on signaling molecules potentially downstre am of LPS receptors in activated macrophages. Our findings indicate that ri bosomal S6 kinase 2 (RSK2), a 90-kDa ribosomal S6 kinase with a critical ro le as an effector of the RAS-mitogen-activated protein kinase pathway and a regulator of immediate early gene transcription is a target for inhibition by the NSAIDs. NSAIDs inhibited the activity of purified RSK2 kinase in vi tro and of RSK2 in mammalian cells and suppressed the phosphorylation of RS K2 substrates cAMP response element binding protein (CREB) and I-kappa B al pha in vivo. Additionally, NaSal inhibited the phosphorylation by RSK2 of C REB and I-kappa B alpha on residues crucial for their transcriptional activ ity in vivo and thus repressed CREB and NF-kappa B-dependent transcription. These experiments suggest that RSK2 is a target for NSAIDs in the inhibiti on of monocyte-specific gene expression and indicate the importance of RSK2 and related kinases in cell regulation, indicating a new area for anti-inf lammatory drug discovery.