CostunolideamelioratescolitisviaspecificinhibitionofHIF1α/glycolysis-mediatedTh17differentiation.
木香酚通过特异性抑制HIF1α/糖酵解介导的Th17分化来改善结肠炎
Abstract
Ulcerativecolitis(UC)isachronicidiopathicinflammatorydisorderofcolon.Costunolide,themainactiveconstituentofRadixAucklandiae,hasbeendemonstratedtopossessanti-inflammatoryandimmunomodulationactivities.TheaimofthisstudyistoinvestigatetheeffectofcostunolideonUCinducedbydextransulfatesodium(DSS).Resultsshowedthatoraladministrationofcostunolidesignificantlyimprovedthediseaseactiveindex(DAI),rescuedthereductionofcolonlength,downregulatedmyeloperoxidase(MPO)activity,alleviatedthepathologicalchanges,anddecreasedthelevelsofproinflammatorycytokinesincolonsofcolitismice.
CostunolidealsorebalancedTh17/Tregcellsincolons,mesentericlymphnodesandspleen,asindicatedbydecreasedpercentagesofTh17cellsandreducedmRNAexpressionsofRorc,Il17a.Interestingly,theinvitroexperimentshowedthatnosignificantchangeindendriticcellmaturation,mRNAexpressionsofIfng,Il6andTregcelldifferentiation,butasignificantdecreasedTh17celldifferentiationwasobserveduponcostunolidetreatment.
UC是一种慢性特发性结肠炎。木香酚，木香的主要活性成分，目前已证明其具有抗炎和免疫调节活性。这项研究的目的是调查木香酚对经DSS诱导出UC的影响。结果显示，口服木香酚可显著改善疾病活动指数（DAI），减轻结肠长度缩短，降低MPO活性，减轻病理变化并降低结肠炎小鼠结肠中促炎细胞因子的水平。木香酚还可以使结肠、肠系膜淋巴结和脾脏中的Th17/Treg细胞重新平衡，主要表现为Th17细胞百分比降低和Rorc、Il17amRNA表达降低。有趣的是，体外实验显示树突状细胞成熟，IFNG、IL6和Treg细胞分化的mRNA表达无明显变化，但在木香酚处理后观察到Th17细胞分化明显降低。
Deepermechanisticstudiesshowedthatcostunolidetriggeredtheprolylhydroxylase2(PHD2)-triggeredprolinehydroxylation-ubiquitination-proteasomedegradationofHIF-1α,whichinturninactivatedglycolyticprocessinTh17ratherthanTregcells.
ThesefindingsclearlysuggestthatinhibitionofHIF-1α-mediatedglycolysisbycostunolideisspecificallyresponsibleforTh17celldifferentiationandsubsequentalleviationofUCandsetsthestageforanewperspectiveonimmune-metabolismtherapyforcolitis.
进一步机理研究表明，木香酚激活了PHD2介导脯氨酸羟化-泛素化-蛋白酶体降解HIF-1α，进而使Th17细胞而不是Treg细胞的糖酵解过程失活。这些发现明确显示，木香酚抑制HIF-1α介导的糖酵解是Th17细胞分化和随后UC缓解的特有原因，并为免疫代谢疗法治疗结肠炎奠定了新基础。
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