A fully dissociated compound of plant origin for inflammatory gene repression

De Bosscher, Karolien ; Van den Berghe, Wim ; Beck, Ilse M. E. ; Van Molle, Wim ; Hennuyer, Nathalie ; Hapgood, Janet ; Liber, Claude ; Staels, Bart ; Louw, Ann ; Haegeman, Guy (PNAS, 2005-11)

The original publication is available at http://www.pnas.org/content/by/year


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-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.

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