Abstract

The present study aimed to evaluate the anti-colitis effect and underlying mechanisms of cardamonin, a natural flavone isolated from Alpinia katsumadai Hayata. The results showed that oral cardamonin significantly inhibited dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice, evidenced by improvement of disease activity index scores, myeloperoxidase activity, length shortening and histopathological changes of colons. A rectal administration of cardamonin also exhibited marked anti-colitis effect, suggesting that oral cardamonin might function in a prototype form. Cardamonin down-regulated levels of IL-1β, TNF-α, IL-6, NLRP3, cleaved caspase-1, ASC, cleaved IL-1β in colons of colitis mice. In vitro , cardamonin inhibited NLRP3 inflammasome activation in THP-1 and bone marrow-derived macrophages. It acted as an AhR activator, enhanced dissociation of AhR/HSP90 complexes, association of AhR/ARNT complexes, AhR nuclear translocation, XRE reporter gene activity, and AhR/ARNT/XRE DNA binding activity in THP-1 cells. The AhR antagonist CH223191 obviously abolished NLRP3 inflammasome activation inhibited by cardamonin. Furthermore, cardamonin elevated levels of Nrf2 and its target genes NQO1, Trx1 , SOD2 , HO-1, and the effect on NQO1 was the most obvious. The relationship of cardamonin-adjusted AhR activation, expressions of Nrf2 and NQO1, and NLRP3 inflammasome activation was confirmed by using CH223191, siAhR, ML385 and siNQO1 , respectively. Finally, CH223191 was shown to abolish amelioration of cardamonin on DSS- and TNBS-induced colitis, inhibition of NLRP3 inflammasome activation and up-regulation of Nrf2 and NQO1 levels in colons. Taken together, cardamonin ameliorated colitis in mice through the activation of AhR/Nrf2/NQO1 pathway and consequent inhibition of NLRP3 inflammasome activation.