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1、THEJOURNALOFBIOLOGICALCHEMISTRYVOL.286,NO.13,pp.11604–11615,April1,2011PrintedintheU.S.A.ElevatedmiR-155PromotesInflammationinCysticFibrosisbyDrivingHyperexpressionofInterleukin-8*□SReceivedforpublication,October28,2010,andinrevisedform,January24,2011Published,JBCPapersinPress,
2、January31,2011,DOI10.1074/jbc.M110.198390‡‡§‡¶SharmisthaBhattacharyya,NagarajaS.Balakathiresan,CliftonDalgard,UshaGutti,DavidArmistead,§§§‡1CathyJozwik,MeeraSrivastava,HarveyB.Pollard,andRoopaBiswas‡§FromtheDepartmentofHealthSystems,Risk,andContingencyManagement,GraduateSchoolo
3、fNursing,andtheDepartmentofAnatomy,PhysiologyandGenetics,SchoolofMedicine,UniformedServicesUniversityoftheHealthSciences,Bethesda,¶Maryland20814andAppliedBiosystems,FosterCity,California94404CysticFibrosis(CF)ischaracterizedbyamassiveproinflam-(CFTR)gene(1–4).CFTRmutations,ofwh
4、ichthemostcom-matoryphenotypeinthelungarisingfromprofoundexpressionmonisF508-CFTR,causeamassiveproinflammatorypheno-ofinflammatorygenes,includinginterleukin-8(IL-8).Wehavetypeinthelung,whichmanifestsintheairwaybyhighlevelsofpreviouslyreportedthatIL-8mRNAisstabilizedinCFlungIL-
5、8andotherproinflammatorycytokinesandchemokinesepithelialcells,resultinginconcomitanthyperexpressionof(5–7).IL-8isthemostpotentknownchemotacticagentforIL-8protein.However,themechanisticlinkbetweenmutationsneutrophils(8)andisconstitutivelysecretedfromCFlungepi-inCFTRandacquisitio
6、noftheproinflammatoryphenotypeinthelialcells(9).TheenhancedsecretionofIL-8seemstobeantheCFairwayhasremainedelusive.Wehypothesizedthatspe-intrinsicpropertyoftheCFepitheliumbecausefetalCFlungcificmicroRNAs(miRNAs)mightmediatethislinkage.Toiden-epitheliumalsospontaneouslysecretesh
7、ighIL-8levelsintothetifythepotentiallink,wescreenedanmiRNAlibraryfordiffer-airwayasearlyasthe15thweekofgestation(10,11).However,entialexpressioninF508-CFTRandwildtypeCFTRlungthemechanismbywhichamutationinCFTRcausesup-regu-epithelialcelllines.Of22differentiallyandsignificantlyl
8、atedlevelsofIL-8expressionremainspoorlyunderstood.expr
