Role of Notch signaling during lipopolysaccharide‐induced preterm labor

[摘要] NotchsignalingpathwaysexerteffectsthroughoutpregnancyandareactivatedinresponsetoTLRligands.ToinvestigatetheroleofNotchsignalinginpretermlabor,Notchreceptors(Notch1–4),itsligandDelta‐likeprotein‐1,transcriptionalrepressorhairyandenhancerofsplit‐1,andNotchderegulatorNumbwereassessed.Pretermlaborwasinitiatedongestationd14.5by1of2methods:1)inflammation‐inducedpretermlabor:intrauterineinjectionofLPS(aTLR4agonist)and2)hormonallyinducedpretermlabor:subcutaneousinjectionofmifepristone.Delta‐likeprotein‐1,Notch1,andhairyandenhancerofsplit‐1wereelevatedsignificantly,andNumbwasdecreasedintheuterusandplacentaofinflammation‐inducedpretermlabormicebutremainedunchangedinhormonallyinducedpretermlaborcomparedwiththeirrespectivecontrols.F4/80+macrophagepolarizationwasskewedintheuterusofinflammation‐inducedpretermlabortowardM1‐positive(CD11c+)anddouble‐positive[CD11c+(M1)andCD206+(M2)]cells.ThisprocessisdependentonactivationofNotchsignaling,asshownbysuppressionofM1andM2macrophage‐associatedcytokinesindecidualmacrophagesinresponsetoγ‐secretaseinhibitor(aninhibitorofNotchreceptorprocessing)treatmentexvivo.γ‐SecretaseinhibitortreatmentalsodiminishedtheLPS‐inducedsecretionofproinflammatorycytokinesandchemokinesindecidualandplacentalcellsculturedexvivo.Furthermore,treatmentwithrecombinantDelta‐likeprotein‐1ligandenhancedtheLPS‐inducedproinflammatoryresponse.Notchligands(Jagged1and2andDelta‐likeprotein‐4)andvascularendothelialgrowthfactoranditsreceptorinvolvedinangiogenesiswerereducedsignificantlyintheuterusandplacentaduringinflammation‐inducedpretermlabor.Theseresultssuggestthatup‐regulationofNotch‐relatedinflammationanddown‐regulationofangiogenesisfactorsmaybeassociatedwithinflammation‐inducedpretermlaborbutnotwithhormonallyinducedpretermlabor...

[学科分类] 生理学

[关键词] inflammation;mifepristone;DLL‐1 ligand;angiogenesis;macrophage polarization