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B-Responsive Genes1
Department of Adult Oncology and Joint Center for Radiation Therapy, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115
Sodium salicylate (NaSal) and other nonsteroidal
anti-inflammatory drugs (NSAIDs) coordinately inhibit the activity
of NF-
B, activate heat shock transcription factor 1 and suppress
cytokine gene expression in activated monocytes and macrophages.
Because our preliminary studies indicated that these effects could be
mimicked by inhibitors of signal transduction, we have studied the
effects of NSAIDs on signaling molecules potentially downstream of LPS
receptors in activated macrophages. Our findings indicate that
ribosomal S6 kinase 2 (RSK2), a 90-kDa ribosomal S6 kinase with a
critical role 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 vitro and of RSK2 in mammalian cells and
suppressed the phosphorylation of RSK2 substrates cAMP response element
binding protein (CREB) and I-B
in vivo. Additionally, NaSal
inhibited the phosphorylation by RSK2 of CREB and I-B on residues
crucial for their transcriptional activity in vivo and thus repressed
CREB and NF-B-dependent transcription. These experiments suggest
that RSK2 is a target for NSAIDs in the inhibition of monocyte-specific
gene expression and indicate the importance of RSK2 and related kinases
in cell regulation, indicating a new area for anti-inflammatory
drug discovery.
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