A fully dissociated compound of plant origin for inflammatory gene repression

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dc.contributor.authorDe Bosscher, Karolien
dc.contributor.authorVan den Berghe, Wim
dc.contributor.authorBeck, Ilse M. E.
dc.contributor.authorVan Molle, Wim
dc.contributor.authorHennuyer, Nathalie
dc.contributor.authorHapgood, Janet
dc.contributor.authorLiber, Claude
dc.contributor.authorStaels, Bart
dc.contributor.authorLouw, Ann
dc.contributor.authorHaegeman, Guy
dc.date.accessioned2011-05-15T16:02:20Z
dc.date.available2011-05-15T16:02:20Z
dc.date.issued2005-11
dc.descriptionThe original publication is available at http://www.pnas.org/content/by/year
dc.description.abstractThe identification of selective glucocorticoid receptor (GR) modifiers, which separate transactivation and transrepression properties, represents an important research goal for steroid pharmacology. Although the gene-activating properties of GR are mainly associated with undesirable side effects, its negative interference with the activity of transcription factors, such as NF-κB, greatly contributes to its antiinflammatory and immune-suppressive capacities. In the present study, we found that Compound A (CpdA), a plant-derived phenyl aziridine precursor, although not belonging to the steroidal class of GR-binding ligands, does mediate gene-inhibitory effects by activating GR. We demonstrate that CpdA exerts an antiinflammatory potential by down-modulating TNF-induced proinflammatory gene expression, such as IL-6 and E-selectin, but, interestingly, does not at all enhance glucocorticoid response element-driven genes or induce GR binding to glucocorticoid response element-dependent genes in vivo. We further show that the specific gene-repressive effect of CpdA depends on the presence of functional GR, displaying a differential phosphorylation status with CpdA as compared with dexamethasone treatment. The antiinflammatory mechanism involves both a reduction of the in vivo DNA-binding activity of p65 as well as an interference with the transactivation potential of NF-κB. Finally, we present evidence that CpdA is as effective as dexamethasone in counter-acting acute inflammation in vivo and does not cause a hyperglycemic side effect. Taken together, this compound may be a lead compound of a class of antiinflammatory agents with fully dissociated properties and might thus hold great potential for therapeutic use. © 2005 by The National Academy of Sciences of the USA.
dc.description.versionArticle
dc.format.extent6 p. : ill.
dc.identifier.citationDe Bosscher, K. et al. 2005. A fully dissociated compound of plant origin for inflammatory gene repression. Proceedings of the National Academy of Sciences of the United States of America, 102(44), 15827-15832, 10.1073/pnas.0505554102.
dc.identifier.issn278424
dc.identifier.other10.1073/pnas.0505554102
dc.identifier.urihttp://hdl.handle.net/10019.1/12419
dc.publisherPNAS
dc.rights.holderAuthor retain the copyright
dc.subjectGlucocorticoidsen_ZA
dc.subjectCytokinesen_ZA
dc.subjectInflammationen_ZA
dc.subjectAnti-inflammatory agentsen_ZA
dc.titleA fully dissociated compound of plant origin for inflammatory gene repression
dc.typeArticle
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