Costunolide ameliorates colitis via specific inhibition of HIF1α/glycolysis-mediated Th17 differentiation

Ulcerative colitis (UC) is a chronic idiopathic inflammatory disorder of colon. Costunolide, the main active constituent of Radix Aucklandiae, has been demonstrated to possess anti-inflammatory and immunomodulation activities. The aim of this study is to investigate the effect of costunolide on UC induced by dextran sulfate sodium (DSS). Results showed that oral administration of costunolide significantly improved the disease active index (DAI), rescued the reduction of colon length, downregulated myeloperoxidase (MPO) activity, alleviated the pathological changes, and decreased the levels of proinflammatory cytokines in colons of colitis mice. Costunolide also rebalanced Th17/Treg cells in colons, mesenteric lymph nodes and spleen, as indicated by decreased percentages of Th17 cells and reduced mRNA expressions of Rorc, Il17a. Interestingly, the in vitro experiment showed that no significant change in dendritic cell maturation, mRNA expressions of Ifng, Il6 and Treg cell differentiation, but a significant decreased Th17 cell differentiation was observed upon costunolide treatment. Deeper mechanistic studies showed that costunolide triggered the prolyl hydroxylase 2 (PHD2)-triggered proline hydroxylation-ubiquitination-proteasome degradation of HIF-1α, which in turn inactivated glycolytic process in Th17 rather than Treg cells. These findings clearly suggest that inhibition of HIF-1α-mediated glycolysis by costunolide is specifically responsible for Th17 cell differentiation and subsequent alleviation of UC and sets the stage for a new perspective on immune-metabolism therapy for colitis.