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

Abstract

The glucocorticoid receptor (GR) is a transcription factor regulating its target genes either positively, through direct binding to the promoter of target genes, or negatively by the interference with the activity of transcription factors involved in proinflammatory gene expression. The well-known adverse effects of glucocorticoids are believed to be mainly caused by their GR-mediated gene-activating properties. Although dimerization of GR is thought to be essential for gene-activating properties, no compound has yet been described which selectively imposes GR monomer formation and interference with other transcription factors. In the present study, we report on a GR-binding, plant-derived compound with marked dissociative properties in rheumatoid arthritis fibroblast-like synoviocytes, which are important effector cells in inflammation and matrix degradation in rheumatoid arthritis. In addition, these findings could be extended in vivo in murine collagen-induced arthritis, in which joint inflammation was markedly inhibited without inducing hyperinsulinemia. Therefore, we conclude that GR monomers are sufficient for inhibition of inflammation in vivo.

Compound A, a Plant Origin Ligand of Glucocorticoid Receptors, Increases Regulatory T Cells and M2 Macrophages to Attenuate Experimental Autoimmune Neuritis with Reduced Side Effects

“…Therefore, in EAN Compound A could directly and indirectly polarize M2 macrophage differentiation to favor EAN outcome. Our study here and findings from other groups showed that Compound A could induce GR nuclear translocation, suggesting that Compound A is a GR ligand (22,23). At present, GR ligands are still the most effective drugs for inflammatory disorders.…”

“…Compound A was dissolved in PBS and the same volume of PBS was given as control. The dosaging of Compound A was comparable to treatment of arthritis in mice (23).…”

“…In our study, mRNA level of hepatic enzymes PEPCK and TAT, which are important for gluconeogenesis, in Compound A-treated EAN rats was much lower than prednisolone-treated EAN rats. It has been reported that Compound A could bind to and inhibit dimerization of GR (23). It is widely hypothesized that the desired anti-inflammatory effects of GCs are mainly caused by the interaction of GR as a monomer with transcription factors that drive proinflammatory gene expression, including NF-B, whereas dimerization of GR is involved in the direct binding onto GRE, resulting in direct transcription of target genes of which the proteins are mostly associated with the wellknown endocrine side effects of GC (17).…”

“…Interestingly, Compound A was reported to be a selective GR ligand that had the anti-inflammatory effects but lacked transactivation potential, indicating that Compound A can greatly reduce inflammation with reduced side effects compared with GCs (22). Recently, it has been reported, that Compound A efficiently attenuates arthritis of mice with reduced side effects (23). In this study, we have investigated the therapeutic effects of Compound A in EAN and its underlying mechanisms.…”

Ginsenoside Rg1, a Novel Glucocorticoid Receptor Agonist of Plant Origin, Maintains Glucocorticoid Efficacy with Reduced Side Effects

“…Both models have been used to test the anti-inflammatory activities of many compounds (10,14,52,53). Our data clearly show an anti-inflammatory function of Rg1 in both the acute and chronic inflammatory models.…”