Kirenol upregulates nuclear Annexin-1 which interacts with NF-κB to attenuate synovial inflammation of collagen-induced arthritis in rats

Ethnopharmacological relevanceKirenol is a diterpenoid compound purified from the Chinese Herba Siegesbeckiae. Siegesbeckiae has been employed for the treatment of arthritis for centuries, its safety and efficacy are documented through a long history of human use.Aim of the studyTo investigate the effects on collagen-induced arthritis (CIA) and anti-inflammatory mechanism of Kirenol.Materials and methodsKirenol was administrated intragastrically in rats after the onset of CIA. Pathological changes were evaluated by paw swelling and histopathology. Concentration of IL-1β in synovial fluid and adrenal corticotropin (ACTH) in plasma were determined by Elisa. Western blot was performed to detect the expression of Annexin-1 and glucocorticoid receptor alpha (GRα) in synovium. NF-κB DNA binding activity was assessed by electrophoretic mobility shift assays (EMSA).ResultsKirenol (1, 2, and 4 mg/kg) and Prednisolone depressed paw swelling and reduced IL-1β of synovial fluid in the CIA rats (p < 0.05 or p < 0.01). Kirenol and Prednisolone upregulated nuclear Annexin-1 and inhibited NF-κB activity in synovium of CIA. The inhibitory effect of Kirenol and Prednisolone on NF-κB activity was enhanced by anti-Annexin-1 Ab. Prednisolone, but not Kirenol, downregulated plasma ACTH and GRα expression significantly (p < 0.01).ConclusionKirenol and Prednisolone can upregulate nuclear Annexin-1 which interacts with NF-κB to inhibit NF-κB activity, reduce cytokines expression and thereby attenuate inflammation of CIA joints. Kirenol does not lead to ACTH or GR downregulation, which is in contrast to classic glucocorticoid Prednisolone. Kirenol shares with GCs similar anti-inflammatory mechanism but bypass the considerable limitation of GCs treatment.