IFN-β Inhibits the Increased Expression of IL-9 during Experimental Autoimmune Uveoretinitis
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IFN-bInhibitstheIncreasedExpressionofIL-9during
ExperimentalAutoimmuneUveoretinitis
YanYang1,2,LipingDu2,MinSun2,AizeKijlstra3,PeizengYang2*
1ZhongshanOphthalmicCenter,SunYat-senUniversity,Guangzhou,P.R.China,2TheFirstAffiliatedHospitalofChongqingMedicalUniversity,ChongqingKey
LaboratoryofOphthalmologyandChongqingEyeInstitute,Chongqing,P.R.China,3EyeResearchInstituteMaastricht,DepartmentofOphthalmology,University
HospitalMaastricht,Maastricht,TheNetherlands
Abstract
Purpose:IthasbeenshownthatIL-9playsaproinflammatoryroleinthepathogenesisofcertainautoimmunediseases.This
studywasdesignedtoinvestigatethepossibleroleofIL-9inthedevelopmentofexperimentalautoimmuneuveoretinitis
(EAU)andtheeffectofIFN-bonitsexpression.
Methods:EAUwasinducedinB10RIIImicebyimmunizationwithinterphotoreceptorretinoid-bindingproteinpeptide161–
180(IRBP161–180).IFN-bwasadministeredsubcutaneouslytoIRBP161–180immunizedmiceeveryotherdayfromdayone
beforeimmunizationtotheendofthestudy.Splenocytesanddraininglymphnode(DLN)cellsfromEAUmiceorcontrol
miceorEAUmicetreatedwithIFN-borPBSwerestimulatedwithanti-CD3/CD28orIRBP161–180for3days.Naı¨veTcells
culturedunderTh1orTh17polarizingconditionswereincubatedinthepresenceorabsenceofIFN-bfor4days.Effector/
memoryTcellswereactivatedbyanti-CD3/CD28inthepresenceorabsenceofIFN-bfor3days.IFN-b-treatedmonocytes
werecoculturedwithnaı¨veTcellsoreffector/memoryTcellsfor3days.CulturesupernatantswerecollectedandIL-9was
detectedbyELISA.
Results:IL-9expressioninsplenocytesandDLNcellswasincreasedinEAUmiceduringtheinflammatoryphaseand
returnedbacktolowerlevelsduringtherecoveryphase.IFN-binvivotreatmentsignificantlyinhibitedEAUactivityin
associationwithadown-regulatedexpressionofIL-9.InvitropolarizedTh1andTh17cellsbothsecretedIL-9andthe
additionofIFN-bsuppressedproductionofIL-9bybothThsubsets.BesideitseffectonpolarizedThcells,IFN-balso
suppressedthesecretionofIL-9byeffector/memoryTcells.However,IFN-b-treatedmonocyteshadnoeffectonthe
productionofIL-9whencoculturedwithnaı¨veoreffector/memoryTcells.
Conclusion:IL-9expressionisincreasedduringEAUwhichcouldbesuppressedbyIFN-b.
Citation:YangY,DuL,SunM,KijlstraA,YangP(2012)IFN-bInhibitstheIncreasedExpressionofIL-9duringExperimentalAutoimmuneUveoretinitis.PLoS
ONE7(10):e48566.doi:10.1371/journal.pone.0048566
Editor:LucienneChatenoud,Universite´ParisDescartes,France
ReceivedJuly31,2012;AcceptedSeptember28,2012;PublishedOctober30,2012
Copyright:ß2012Yangetal.Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense,whichpermits
unrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalauthorandsourcearecredited.
Funding:ThisworkwassupportedbyChongqingKeyLaboratoryofOphthalmology(CSTC,2008CA5003)http://www.ctin.ac.cn/View.aspx?id=14380,Key
ProjectofNationalNaturalScienceFoundationofChina(81130019)http://159.226.244.22/portal/Proj_List.asp,NationalNaturalScienceFoundationofChina
(81070722)http://159.226.244.22/portal/Proj_List.asp,NationalNaturalScienceFoundationProject(30973242)http://159.226.244.22/portal/Proj_List.asp,Program
fortheTrainingofaHundredOutstandingS&TLeadersofChongqingMunicipality,http://cqkjdj.cstc.gov.cn/View.aspx?id=1000,andFundforPAR-EUScholars
Program,http://www.cqhrss.gov.cn/u/cqhrss/news_37398.shtml.Thefundershadnoroleinstudydesign,datacollectionandanalysis,decisiontopublish,or
preparationofthemanuscript.
CompetingInterests:Theauthorshavedeclaredthatnocompetinginterestsexist.
*E-mail:peizengycmu@126.com
Introduction
Experimentalautoimmuneuveoretinitis(EAU)servesasan
animalmodelforhumanuveitisandiswidelyusedtodissectthe
immunopathologicalmechanismsinuveitisandtodevelop
preventiveortherapeuticstrategies[1].EAUcanbeinducedby
immunizationwithuveitogenicretinalantigens,suchasretinalS
antigen[2],interphotoreceptorretinal-bindingprotein(IRBP)[3–
4]ortheirpolypeptides,orbytheadoptivetransferofuveitogenic
Tcells[5–6],suggestingthatuveitisisaTcell-mediated,organ-
specificautoimmunedisease.IFN-c-producingTh1cellsandIL-
17-producingTh17cellsaretwotypesofinflammatoryTcellsthat
playimportantrolesinthedevelopmentofEAU[7–9].
Recently,aneweffectorTcellsubset,Th9cells,hasbeen
identified[10–11],butitsroleinthepathogenesisofuveitisisnotyetclear.DrivenbythecombinedeffectsofTGF-bandIL-4,Th9
cellsproducelargeamountsofIL-9andIL-10.However,IL-9is
notonlyproducedbyTh9cells.IL-9wasprimarilydescribedin
miceandhumansasaTh2cytokine[12],butrecentstudieshave
identifieditasadominantcytokineproducedbyTh17cells[13–
14].IL-9hasbeenshowntomediateTh17celldifferentiation
[13,15],andinananimalmodel,IL-9neutralizationandIL-9
receptordeficiencyattenuatesexperimentalautoimmuneenceph-
alitis[14–15].ThesefindingssuggestthatIL-9mayplay
