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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 ER 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 ER-binding ligands, does mediate gene-inhibitory effects by activating ER. 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 ER binding to glucocorticoid response element-dependent genes in viva. We further show that the specific gene-repressive effect of CpdA depends on the presence of functional ER, displaying a differential phosphorylation status with CpdA as compared with dexamethasone treatment. The antiinflammatory mechanism involves both a reduction of the in viva 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 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. [ABSTRACT FROM AUTHOR]