Anti-inflammatory actions of Caesalpinin M2 in experimental colitis as a selective glucocoricoid receptor modulator

Although repression of inflammatory gene expression makes glucocorticoids (GCs) powerful anti-inflammatory agents, side effects limit usage and drive the search for improved glucocorticoid receptor (GR) ligands. It has been postulated that the anti-inflammatory effects of GCs are primarily mediated by GR's activity in transrepressing major inflammation pathways such as NF-κB pathway, whereas their side effects are mostly mediated by GR's transactivation. In this study, we found that Caesalpinin M2 (C-M2), a cassane furanoditerpene isolated from a Chinese medical plant, exerts an anti-inflammatory potential both in vitro and in vivo. C-M2 inhibited the expression of proinflammatory cytokine IL-1β and IL-6 in LPS-activated bone marrow-derived macrophages. Meanwhile, C-M2 treatment attenuated DSS-induced experimental acute colitis in mice and did not cause side effects, such as spleen involution, like dexamethasone treatment. Molecular docking and cellular thermal shift assay demonstrated that C-M2 could bind to GR in the ligand binding site. We showed that C-M2 mediates gene-inhibitory effects by activating GR. More importantly, C-M2 failed to induce GR binding to glucocorticoid response element-dependent genes and in turn activate their transcription. But it did repress NF-κB-dependent transcription by facilitating the interaction between GR and p65. Taken together, this non-steroidal compound of plant origin may exert anti-inflammatory actions as a selective GR modulator and might hold great potential for therapeutic use in inflammatory diseases.