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: 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 102 Issue 44 Pg. 15827-32 (Nov 01 2005) ISSN: 0027-8424 [Print] United States
• PMID: 16243974 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Aziridines
• Cytokines
• NF-kappa B
• Plant Extracts
• Receptors, Glucocorticoid
• Tumor Necrosis Factor-alpha
• Dexamethasone
• eIF-2 Kinase

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Aziridines (pharmacology)
• Cell Line
• Cytokines (genetics)
• Dexamethasone (pharmacology)
• Down-Regulation (drug effects, genetics)
• Humans
• Inflammation (drug therapy, genetics)
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Phosphorylation (drug effects)
• Plant Extracts (chemistry)
• Receptors, Glucocorticoid (agonists, metabolism)
• Transfection
• Tumor Necrosis Factor-alpha (pharmacology)
• eIF-2 Kinase (metabolism)