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-B, 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 geneinhibitory effects by activating GR. We demonstrate that CpdA exerts an antiinflammatory potential by down-modulating TNFinduced proinflammatory gene expression, such as IL-6 and Eselectin, 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-B. 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.cytokine ͉ glucocorticoid receptor ͉ inflammation ͉ NF-B

Anti-inflammatory functions of glucocorticoid-induced genes

“…For these reasons it is important to show that GCs do not impair the interaction of NFκB with the relevant cognate site in vivo, an important proposition of the transrepression model. Accordingly, GCs did not inhibit binding of NFκB to the 5' regions of the chemokines CXCL1 and CXCL9 (Ogawa et al, 2005), ICAM-1 (Liden et al, 2000) or CXCL8 (De Bosscher et al, 2005;Luecke and Yamamoto, 2005;Nissen and Yamamoto, 2000). To our knowledge, effects of GCs on NFκB recruitment at other transrepressed genes have not been reported.…”

A Plant-Derived Ligand Favoring Monomeric Glucocorticoid Receptor Conformation with Impaired Transactivation Potential Attenuates Collagen-Induced Arthritis

“…In the acute model of arthritis (zymosan-induced arthritis model), i.p. administration of 300 g was determined to be highly effective (22). In CIA, a daily dose of 100 g injected i.p.…”

“…CpdA, or 2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride, is a stable analog of the hydroxyphenyl aziridine precursor found in the Namibian shrub Salsola tuberculatiformis Botschantzev (20,21). We previously described the antiinflammatory effects and the lack of transactivation by CpdA in a fibrosarcoma and a lung carcinoma cell line (22). Additionally, CpdA was able to prevent the onset of paw swelling in a zymosaninduced arthritis model, which is based on the activation of the innate immune system.…”

Selective glucocorticoid receptor agonists (SEGRAs): Novel ligands with an improved therapeutic index

“…2, Table 1), is a stable analogue of the hydroxyl phenyl aziridine precursor found in the Namibian shrub Salsola tuberculatiformis Botschantzev and exhibits a dissociated profile with respect to the GR (De Bosscher et al, 2005). Compound A, described by Haegeman and coworkers, is the first example of such a dissociated compound isolated from natural sources.…”

“…Furthermore, the authors showed that it was possible to relate this in vitro dissociation to an in vivo context. According to the publication, Compound A is as active an antiinflammatory as dexamethasone in a zymosan-induced paw edema model in mice but induces no increase in the blood glucose level (De Bosscher et al, 2005).…”