Diosgenin, a natural steroidal saponin, suppresses COX-2 and mPGES-1 via the glucocorticoid receptor and improves LPS-induced liver injury in mice

Background and objectives: Prostaglandin (PG) E2, one of the pro-inflammatory lipid mediators, induces acute and chronic inflammation. In some pathophysiological conditions, cyclooxygenase (COX)-2 and microsomal PGE synthase (mPGES)-1 are transiently induced, leading to PGE2 overproduction. We previously found novel anti-inflammatory and anti-carcinogenic effects via the downregulation of COX-2 and mPGES-1 in a wild yam, Dioscorea japonica. Additionally, diosgenin, a steroidal saponin, was one of the potential substances in wild yam. In this study, we examined whether diosgenin suppressed COX-2 through the glucocorticoid receptor (GR), and ameliorated the inflammation in the lipopolysaccharide (LPS)-induced mouse acute liver injury. Methods: Human non-small-cell lung carcinoma A549 cells were incubated with diosgenin (100 or 1000 nM), and with/without RU486 (0-100 nM) as GR antagonist. Mouse models of acute liver injury induced by LPS (10 mg/kg/day i.p.) were administered diosgenin (100 μmol/kg/day i.p.). Protein and mRNA expression levels were analyzed by western blotting and quantitative RT-PCR, respectively. Immunocytochemistry and immunohistchemistry were carried out by multiple immunofluorescence microscopy using specific antibodies against COX-2, mPGES-1, nuclear factor-kappa B (NF-κB; a potent transcription factor of COX-2) and F4/80 (a macrophage marker). Results: We demonstrated that diosgenin suppressed COX-2 in A549 cells via NF-κB translocation and the effects were reversed by RU486. In LPS-induced mouse liver injury, COX-2 and mPGES-1 were induced and localized in sinusoidal macrophages and endothelial cells; however, diosgenin administration significantly suppressed Ptgs2 (COX-2) and Ptges (mPGES-1) expression and decreased COX-2 and mPGES-1 immunopositive cells in the sinusoids. Multiple immunohistochemical analyses showed that diosgenin had an effect on COX-2 and mPGES-1, particularly in the macrophages. Conclusions: These findings suggested that diosgenin downregulated COX-2 and mPGES-1 via the GR and suppressed COX-2 and mPGES-1 in the macrophages of LPS-induced acute mouse liver injury. Diosgenin may be an effective alternative therapy as a food-derived bioactive compound; it acts in a cell-specific manner without any adverse effects, such as thrombosis.