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Salicylic acid and aspirin inhibit the activity of RSK2 kinase and repress RSK2-dependent transcription of cyclic AMP response element binding protein- and NF-kappa B-responsive genes.
J Immunol. 1999 Nov 15; 163(10):5608-16.JI

Abstract

Sodium salicylate (NaSal) and other nonsteroidal anti-inflammatory drugs (NSAIDs) 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 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-kappa B alpha in vivo. Additionally, NaSal inhibited the phosphorylation by RSK2 of CREB and I-kappa B alpha on residues crucial for their transcriptional activity in vivo and thus repressed CREB and NF-kappa 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.

Authors+Show Affiliations

Department of Adult Oncology, Joint Center for Radiation Therapy, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10553090

Citation

Stevenson, M A., et al. "Salicylic Acid and Aspirin Inhibit the Activity of RSK2 Kinase and Repress RSK2-dependent Transcription of Cyclic AMP Response Element Binding Protein- and NF-kappa B-responsive Genes." Journal of Immunology (Baltimore, Md. : 1950), vol. 163, no. 10, 1999, pp. 5608-16.
Stevenson MA, Zhao MJ, Asea A, et al. Salicylic acid and aspirin inhibit the activity of RSK2 kinase and repress RSK2-dependent transcription of cyclic AMP response element binding protein- and NF-kappa B-responsive genes. J Immunol. 1999;163(10):5608-16.
Stevenson, M. A., Zhao, M. J., Asea, A., Coleman, C. N., & Calderwood, S. K. (1999). Salicylic acid and aspirin inhibit the activity of RSK2 kinase and repress RSK2-dependent transcription of cyclic AMP response element binding protein- and NF-kappa B-responsive genes. Journal of Immunology (Baltimore, Md. : 1950), 163(10), 5608-16.
Stevenson MA, et al. Salicylic Acid and Aspirin Inhibit the Activity of RSK2 Kinase and Repress RSK2-dependent Transcription of Cyclic AMP Response Element Binding Protein- and NF-kappa B-responsive Genes. J Immunol. 1999 Nov 15;163(10):5608-16. PubMed PMID: 10553090.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Salicylic acid and aspirin inhibit the activity of RSK2 kinase and repress RSK2-dependent transcription of cyclic AMP response element binding protein- and NF-kappa B-responsive genes. AU - Stevenson,M A, AU - Zhao,M J, AU - Asea,A, AU - Coleman,C N, AU - Calderwood,S K, PY - 1999/11/24/pubmed PY - 1999/11/24/medline PY - 1999/11/24/entrez SP - 5608 EP - 16 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J. Immunol. VL - 163 IS - 10 N2 - Sodium salicylate (NaSal) and other nonsteroidal anti-inflammatory drugs (NSAIDs) 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 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-kappa B alpha in vivo. Additionally, NaSal inhibited the phosphorylation by RSK2 of CREB and I-kappa B alpha on residues crucial for their transcriptional activity in vivo and thus repressed CREB and NF-kappa 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. SN - 0022-1767 UR - https://www.unboundmedicine.com/medline/citation/10553090/Salicylic_acid_and_aspirin_inhibit_the_activity_of_RSK2_kinase_and_repress_RSK2_dependent_transcription_of_cyclic_AMP_response_element_binding_protein__and_NF_kappa_B_responsive_genes_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=10553090 DB - PRIME DP - Unbound Medicine ER -