Beta2-Adrenoceptor Stimulation Suppresses TLR9-Dependent IFNA1 Secretion in Human Peripheral Blood Mononuclear Cells.docVIP

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Beta2-Adrenoceptor Stimulation Suppresses TLR9-Dependent IFNA1 Secretion in Human Peripheral Blood Mononuclear Cells.doc

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Beta2-Adrenoceptor Stimulation Suppresses TLR9-Dependent IFNA1 Secretion in Human Peripheral Blood Mononuclear Cells

Beta2-AdrenoceptorStimulationSuppressesTLR9- DependentIFNA1SecretioninHumanPeripheralBlood MononuclearCells TobiasHilbert.,JosefBongartz.,ChristinaWeisheit,PascalKnu¨fermann,GeorgBaumgarten, AndreasHoeft,JensM.Poth* DepartmentofAnesthesiologyandIntensiveCareMedicine,UniversityHospitalBonn,Germany Abstract Introduction: IFNA1 (interferon alpha) is a key cytokine regulating the activity of numerous immune cells. Plasmacytoid dendritic cells (pDCs) as natural interferon-producing cells play critical roles as sensors of pathogens and link innate to adaptive immunity. CpG motifs within DNA sequences activating toll-like receptor 9 (TLR9) arethemain stimulieliciting IFNA1 secretion from pDCs. Adrenergic substances are capable of differentially modulating the response from various immunecells.Hence,theaimofthisstudywastoexaminehowadrenoceptorstimulationinfluencesTLR9-inducedIFNA1 secretionfromhumanpDCs. Methods:PBMCsgeneratedfromhumanwholebloodandpDCsenrichedfrombuffycoatswerestimulatedwithLPSand CpG-ODN2336inthepresenceorabsenceofepinephrineanddifferentadrenoceptorantagonists.SecretionofTNFand IFNA1 was measured by ELISA. Flow cytometry was used to determine efficacy of pDC enrichment and adrenoceptor expression of PBMC subsets. The influence of modified IFNA1 secretion on NK cell activity was evaluated using a colorimetrictumorcelllysisassay. Results: TLR9-induced IFNA1 secretion as well as TLR4-induced TNF secretion from PBMCs was dose-dependently attenuatedbycoincubationwithepinephrine.Combinationwithdifferentspecificadrenoceptorantagonistsrevealedthat this effect was mediated by the adrenoceptor b2 (ADRB2). Since flow cytometric analysis could exclude the presence of ADRB2 on pDCs, highly enriched pDCs lacked any visible impact of adrenoceptor stimulation on TLR9-induced IFNA1 release.CombinationofpDCswithPBMCsrestoredtheeffect,evenwhentheywereseparatedbyapermeablemembrane. SuppressionofTLR9-mediatedIFNA1secretionfromPBMCsbyadrenoceptorstimulationreducedthelyticacti