促炎细胞因子
结肠炎
RAR相关孤儿受体γ
髓过氧化物酶
脾脏
细胞分化
化学
细胞生长
免疫系统
炎症
癌症研究
生物
免疫学
生物化学
FOXP3型
基因
作者
Qi Lv,Xing Yao,Dong Dong,Yang Hu,Qingzhu Chen,Linhui Zhai,Lihong Hu,Yinan Zhang
标识
DOI:10.1016/j.intimp.2021.107688
摘要
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.
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