Regulation of the CCL2 Gene in Pancreatic β-Cells by IL-1β and Glucocorticoids Role of MKP-1 英文参考文献.docVIP

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Regulation of the CCL2 Gene in Pancreatic β-Cells by IL-1β and Glucocorticoids Role of MKP-1 英文参考文献.doc

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Regulation of the CCL2 Gene in Pancreatic β-Cells by IL-1β and Glucocorticoids Role of MKP-1 英文参考文献

RegulationoftheCCL2GeneinPancreaticb-CellsbyIL- 1bandGlucocorticoids:RoleofMKP-1 SusanJ.Burke1,MatthewR.Goff1,BarrettL.Updegraff1,DanhongLu2,PatriciaL.Brown3, StevenC.MinkinJr3,JohnP.Biggerstaff3,LingZhao1,5,MichaelD.Karlstad1,4,5,J.JasonCollier1,5 * 1DepartmentofNutrition,UniversityofTennessee,Knoxville,Tennessee,UnitedStatesofAmerica,2SarahW.StedmanNutritionandMetabolismCenter,DukeUniversity MedicalCenter,Durham,NorthCarolina,UnitedStatesofAmerica,3AdvancedMicroscopyandImagingCenter,UniversityofTennessee,Knoxville,Tennessee,United States of America, 4Department of Surgery, Graduate School of Medicine, University of Tennessee Medical Center, Knoxville, Tennessee, United States of America, 5UniversityofTennesseeObesityResearchCenter,Knoxville,Tennessee,UnitedStatesofAmerica Abstract Releaseofpro-inflammatorycytokinesfrombothresidentandinvadingleukocyteswithinthepancreaticisletsimpactsthe development of Type 1 diabetes mellitus. Synthesis and secretion of the chemokine CCL2 from pancreatic b-cells in responsetopro-inflammatorysignalingpathwaysinfluencesimmunecellrecruitmentintothepancreaticislets.Therefore, weinvestigatedthepositiveandnegativeregulatorycomponentscontrollingexpressionoftheCCL2geneusingisolated ratisletsandINS-1-derivedb-celllines.WediscoveredthatactivationoftheCCL2genebyIL-1brequiredthep65subunitof NF-kBandwasdependentongenomicresponseelementslocatedinthe23.6kbregionoftheproximalgenepromoter. CCL2 gene transcription in response to IL-1b was blocked by pharmacological inhibition of the IKKb and p38 MAPK pathways.TheIL-1b-mediatedincreaseinCCL2secretionwasalsoimpairedbyp38MAPKinhibitionandbyglucocorticoids. Moreover,multiplesyntheticglucocorticoidsinhibitedtheIL-1b-stimulatedinductionoftheCCL2gene.Inductionofthe MAP Kinase Phosphatase-1 (MKP-1) gene by glucocorticoids or by adenoviral-mediated overexpression decreased p38 MAPK phosphorylation, which diminished CCL2 gene expression, promoter activity, and release of CCL2 protein. We concludethatglucoco