A fully dissociated compound of plant origin for inflammatory gene repression.
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.
De Bosscher
Karolien
K
Laboratory of Eukaryotic Gene Expression and Signal Transduction, Department of Molecular Biology, Ghent University, K. L. Ledeganckstraat 35, B-9000 Ghent, Belgium.
Vanden Berghe
Wim
W
Beck
Ilse M E
IM
Van Molle
Wim
W
Hennuyer
Nathalie
N
Hapgood
Janet
J
Libert
Claude
C
Staels
Bart
B
Louw
Ann
A
Haegeman
Guy
G
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
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