IL‐4 reduces the proangiogenic capacity of macrophages by down‐regulating HIF‐1α translation

[摘要] MΦshowahighlyversatilephenotypedependingonthereceivingmicroenvironmentalstimuli.MΦphenotypesaregroupedinthreesubcategories.OneisclassicallyactivatedMΦ(afterstimulationwithLPSorIFN‐γ),andtwoarealternativelyactivatedforms,knownaswound‐healingMΦ(inducedbyIL‐4/IL‐13)andregulatoryMΦ(inducedbyIL‐10/TGF‐β).Besidescytokines,hypoxiadefinesMΦfunctions,asshownforclassicallyactivatedcells.Yet,littleisknownabouttheroleofhypoxiaandHIF‐1and‐2inwound‐healingorregulatoryMΦ.HIFtargetgenes(suchasADM),analyzedinalternativelyactivatedMΦfromWTandHIF−/−mice,wereregulatedpredominantlybyHIF‐1andconsistentlyshowedreducedhypoxicinductioninMΦstimulatedwithIL‐4.Togainmechanisticinsights,weanalyzedHIFexpressioninpolarizedMΦ.ClassicallyactivatedMΦarecharacterizedbytheinductionofHIF‐1αbutreductionofHIF‐2αmRNAandprotein,whereaswound‐healingMΦdecreasedHIF‐1αproteinexpressionwithoutalteringmRNAlevels.AnalysisofproteinstabilityandexpressionafterproteasomalinhibitionpointedtotranslationalregulationofHIF‐1αinwound‐healingMΦ.Followingangiogenic‐sproutingusingembryonicstemcellsexposedtosupernatantsofMΦincubatedwithIL‐4underhypoxia,shortersproutswererevealedcomparedwithsupernatantsofhypoxicMΦwithoutIL‐4.Conclusively,IL‐4reducesHIF‐1αtranslationandthus,itsactivityinMΦandconcomitantly,attenuatestheirabilitytopromoteangiogenesisunderhypoxicconditions...

[学科分类] 生理学

[关键词] wound healing;classically activated;regulatory;hypoxia