A fully dissociated compound of plant origin for inflammatory gene repression

• DOI: 10.1073/pnas.0505554102
• Publication Date: 2005-10-26T08:13:26Z
• Authors: Karolien De Bosscher; Wim Vanden Berghe; Ilse M. E. Beck; Wim Van Molle; Nathalie Hennuyer; Janet Hapgood; Claude Libert; Bart Staels; Ann Louw; Guy Haegeman
• Keywords: 0301 basic medicine; Aziridines; 610; Down-Regulation; Transfection; Dexamethasone; Cell Line; Mice; eIF-2 Kinase; 03 medical and health sciences; Receptors, Glucocorticoid; Animals; Humans; Phosphorylation; Glucocorticoids; Anti-inflammatory agents; Inflammation; Plant Extracts; Tumor Necrosis Factor-alpha; Anti-Inflammatory Agents, Non-Steroidal; NF-kappa B; 540; 3. Good health; Mice, Inbred C57BL; Cytokines

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 genesin 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 thein vivoDNA-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 inflammationin vivoand 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.