Role of Notch signaling during lipopolysaccharide‐induced preterm labor

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

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

DOI  :  10.1189/jlb.3HI0515-200RR

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 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...

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