LAUSR

Graphical abstract Figure. No Caption available. Abstract 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‐&kgr;B 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‐1&bgr; 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‐&kgr;B‐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.