A novel tylophorine analog W‐8 up‐regulates forkhead boxP3 expression and ameliorates murine colitis

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: TGF‐;    β;    Treg;    inflammatory bowel diseases;    immune therapy;   

DOI  :  10.1189/jlb.0812402

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Tylophorineandanalogsarephenanthroindolizidinealkaloids,severalofwhichhavebeenreportedtohaveanticancer,antiviral,andanti‐inflammatoryproperties.However,theirfunctionintheimmunesystemremainswidelyunknown.TranscriptionfactorFoxp3iscriticalforthedevelopmentandfunctionofTreg,whichdown‐regulatestheimmunesystemandmaintainstolerancetoself‐antigens.Inthepresentstudy,wedefinedanoveltylophorineanalog,W‐8,enhancedTGF‐β‐inducedFoxp3expressionatthemRNAandtheproteinlevels.Interestingly,W‐8synergisticallyincreasedthelevelofTGF‐β‐inducedp‐Smad3throughinhibitionoftheAKT/mTORpathwayandenhancedthedemethylationofthepromoterregionoftheFoxp3throughinhibitionoftheERKpathwayandDNMT1expression.Moreover,administrationofW‐8suppressedTNBS‐inducedmurinecolitisandincreasedTregsinlymphoidtissues.Finally,W‐8enhancedconversionofnaïveTcellstoTregsinvivo.Insummary,ourresultsdefinedanovelcompoundthatenhancedFoxp3expressionthroughtranscriptionalandepigeneticprograms,anditmightserveasatherapeuticagentforinflammatorydiseases...

【 授权许可】

CC BY