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Article: Analysis of the dissociated steroid RU24858 does not exclude a role for inducible genes in the anti-inflammatory actions of glucocorticoids

TitleAnalysis of the dissociated steroid RU24858 does not exclude a role for inducible genes in the anti-inflammatory actions of glucocorticoids
Authors
Issue Date2006
PublisherAmerican Society for Pharmacology and Experimental Therapeutics. The Journal's web site is located at http://www.molpharm.org
Citation
Molecular Pharmacology, 2006, v. 70 n. 6, p. 2084-2095 How to Cite?
AbstractAlthough repression of inflammatory gene expression makes glucocorticoids powerful anti-inflammatory agents, side effects limit usage and drive the search for improved glucocorticoid receptor (GR) ligands. In A549 pulmonary cells, dexamethasone and the prototypical dissociated ligand RU24858 (Mol Endocrinol 11:1245-1255, 1997) repress interleukin (IL)-1β-induced expression of cyclooxygenase (COX)-2 and IL-8. Although RU24858 is a weaker GR ligand, both glucocorticoids showed similar efficacies on transrepression of nuclear factor κB (NF-κB)-dependent transcription, whereas RU24858 yielded less than 12% of the response to dexamethasone on a classic glucocorticoid response element (GRE) reporter (transactivation). Modest NF-κB-dependent transrepression (∼40%), along with analysis of IL-8 transcription rate and the accumulation of unspliced nuclear RNA, indicates that transrepression does not fully account for the repression of genes such as IL-8. This was confirmed by the finding that mRNA degradation is increased by both dexamethasone and RU24858. Analysis of IL-1β-induced steady-state mRNA levels for IL-8 and COX-2 show that dexamethasone- and RU24858-dependent repression of these genes is attenuated by inhibitors of transcription and protein synthesis. Because similar effects were observed with respect to COX-2 and IL-8 protein expression, we conclude that glucocorticoid-dependent gene expression is necessary for repression by both glucocorticoids. Despite RU24858 being defective at classic GRE-dependent transactivation, both dexamethasone and RU24858 induced the expression of potentially anti-inflammatory genes and metabolic genes, suggesting the importance of nontraditional glucocorticoid-dependent gene expression. Thus, classic transactivation- and transrepression-based screens for anti-inflammatory "dissociated" GR ligands may be flawed because they may not reflect the effects on real glucocorticoid-inducible genes. Copyright © 2006 The American Society for Pharmacology and Experimental Therapeutics.
Persistent Identifierhttp://hdl.handle.net/10722/163045
ISSN
2015 Impact Factor: 3.931
2015 SCImago Journal Rankings: 2.047
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorChivers, JEen_US
dc.contributor.authorGong, Wen_US
dc.contributor.authorKing, EMen_US
dc.contributor.authorSeybold, Jen_US
dc.contributor.authorMak, JCen_US
dc.contributor.authorDonnelly, LEen_US
dc.contributor.authorHolden, NSen_US
dc.contributor.authorNewton, Ren_US
dc.date.accessioned2012-09-05T05:26:55Z-
dc.date.available2012-09-05T05:26:55Z-
dc.date.issued2006en_US
dc.identifier.citationMolecular Pharmacology, 2006, v. 70 n. 6, p. 2084-2095en_US
dc.identifier.issn0026-895Xen_US
dc.identifier.urihttp://hdl.handle.net/10722/163045-
dc.description.abstractAlthough repression of inflammatory gene expression makes glucocorticoids powerful anti-inflammatory agents, side effects limit usage and drive the search for improved glucocorticoid receptor (GR) ligands. In A549 pulmonary cells, dexamethasone and the prototypical dissociated ligand RU24858 (Mol Endocrinol 11:1245-1255, 1997) repress interleukin (IL)-1β-induced expression of cyclooxygenase (COX)-2 and IL-8. Although RU24858 is a weaker GR ligand, both glucocorticoids showed similar efficacies on transrepression of nuclear factor κB (NF-κB)-dependent transcription, whereas RU24858 yielded less than 12% of the response to dexamethasone on a classic glucocorticoid response element (GRE) reporter (transactivation). Modest NF-κB-dependent transrepression (∼40%), along with analysis of IL-8 transcription rate and the accumulation of unspliced nuclear RNA, indicates that transrepression does not fully account for the repression of genes such as IL-8. This was confirmed by the finding that mRNA degradation is increased by both dexamethasone and RU24858. Analysis of IL-1β-induced steady-state mRNA levels for IL-8 and COX-2 show that dexamethasone- and RU24858-dependent repression of these genes is attenuated by inhibitors of transcription and protein synthesis. Because similar effects were observed with respect to COX-2 and IL-8 protein expression, we conclude that glucocorticoid-dependent gene expression is necessary for repression by both glucocorticoids. Despite RU24858 being defective at classic GRE-dependent transactivation, both dexamethasone and RU24858 induced the expression of potentially anti-inflammatory genes and metabolic genes, suggesting the importance of nontraditional glucocorticoid-dependent gene expression. Thus, classic transactivation- and transrepression-based screens for anti-inflammatory "dissociated" GR ligands may be flawed because they may not reflect the effects on real glucocorticoid-inducible genes. Copyright © 2006 The American Society for Pharmacology and Experimental Therapeutics.en_US
dc.languageengen_US
dc.publisherAmerican Society for Pharmacology and Experimental Therapeutics. The Journal's web site is located at http://www.molpharm.orgen_US
dc.relation.ispartofMolecular Pharmacologyen_US
dc.subject.meshAnti-Inflammatory Agents - Pharmacologyen_US
dc.subject.meshBase Sequenceen_US
dc.subject.meshCell Lineen_US
dc.subject.meshDna Primersen_US
dc.subject.meshDactinomycin - Pharmacologyen_US
dc.subject.meshDexamethasone - Pharmacologyen_US
dc.subject.meshDinoprostone - Metabolismen_US
dc.subject.meshGene Expression Regulation - Drug Effectsen_US
dc.subject.meshHumansen_US
dc.subject.meshHydroxycorticosteroids - Pharmacologyen_US
dc.subject.meshRna, Messenger - Geneticsen_US
dc.subject.meshReverse Transcriptase Polymerase Chain Reactionen_US
dc.subject.meshTranscription, Geneticen_US
dc.titleAnalysis of the dissociated steroid RU24858 does not exclude a role for inducible genes in the anti-inflammatory actions of glucocorticoidsen_US
dc.typeArticleen_US
dc.identifier.emailMak, JC:judymak@hku.hken_US
dc.identifier.authorityMak, JC=rp00352en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1124/mol.106.025841en_US
dc.identifier.pmid16988013en_US
dc.identifier.scopuseid_2-s2.0-33751099074en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-33751099074&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume70en_US
dc.identifier.issue6en_US
dc.identifier.spage2084en_US
dc.identifier.epage2095en_US
dc.identifier.isiWOS:000242135700027-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridChivers, JE=6603554380en_US
dc.identifier.scopusauthoridGong, W=8283482500en_US
dc.identifier.scopusauthoridKing, EM=15065450700en_US
dc.identifier.scopusauthoridSeybold, J=7004365794en_US
dc.identifier.scopusauthoridMak, JC=7103323094en_US
dc.identifier.scopusauthoridDonnelly, LE=7102000743en_US
dc.identifier.scopusauthoridHolden, NS=8073803500en_US
dc.identifier.scopusauthoridNewton, R=7401831692en_US

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