title: A fully dissociated compound of plant origin for inflammatory gene repression.
abstract: The 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-kappaB, 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-kappaB. Finally, we present evidence that CpdA is as effective as dexamethasone in counteracting 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.
authors.affiliation: Laboratory of Eukaryotic Gene Expression and Signal Transduction, Department of Molecular Biology, Ghent University, K. L. Ledeganckstraat 35, B-9000 Ghent, Belgium.
authors.forename: Karolien
authors.initials: K
authors.lastname: De Bosscher
authors.forename: Wim
authors.initials: W
authors.lastname: Vanden Berghe
authors.forename: Ilse M E
authors.initials: IM
authors.lastname: Beck
authors.forename: Wim
authors.initials: W
authors.lastname: Van Molle
authors.forename: Nathalie
authors.initials: N
authors.lastname: Hennuyer
authors.forename: Janet
authors.initials: J
authors.lastname: Hapgood
authors.forename: Claude
authors.initials: C
authors.lastname: Libert
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Ann
authors.initials: A
authors.lastname: Louw
authors.forename: Guy
authors.initials: G
authors.lastname: Haegeman
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001388:Aziridines / Q000494:pharmacology*; D002460:Cell Line; D016207:Cytokines / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000737:chemistry; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001388:Aziridines; D016207:Cytokines; D016328:NF-kappa B; D010936:Plant Extracts; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D019892:eIF-2 Kinase