Multi-Scale In Vivo Systems Analysis Reveals the Influence of Immune Cells on TNF-α-Induced Apoptosis in the Intestinal Epithelium 英文参考文献.docVIP

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Multi-Scale In Vivo Systems Analysis Reveals the Influence of Immune Cells on TNF-α-Induced Apoptosis in the Intestinal Epithelium 英文参考文献.doc

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Multi-Scale In Vivo Systems Analysis Reveals the Influence of Immune Cells on TNF-α-Induced Apoptosis in the Intestinal Epithelium 英文参考文献

Multi-ScaleInVivoSystemsAnalysisRevealsthe InfluenceofImmuneCellsonTNF-a-InducedApoptosis intheIntestinalEpithelium KenS.Lau1,2,3,4,5,6,VirnaCortez-Retamozo3,SarahR.Philips1,2,3,MikaelJ.Pittet3, DouglasA.Lauffenburger5,6,KevinM.Haigis1,2,3,4 * 1MolecularPathologyUnit,MassachusettsGeneralHospital,Charlestown,Massachusetts,UnitedStatesofAmerica,2CenterforCancerResearch,MassachusettsGeneral Hospital,Charlestown,Massachusetts,UnitedStatesofAmerica,3CenterforSystemsBiology,MassachusettsGeneralHospital,Boston,Massachusetts,UnitedStatesof America,4DepartmentofPathology,HarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica,5DepartmentofBiologicalEngineering,Massachusetts Institute ofTechnology,Cambridge,Massachusetts,UnitedStatesofAmerica, 6KochInstituteforIntegrativeCancerResearch,MassachusettsInstituteofTechnology, Cambridge,Massachusetts,UnitedStatesofAmerica Abstract Intestinal epithelial cells exist within acomplex environment that affects how they interpret andrespond to stimuli. We have applied a multi-scale in vivo systems approach to understand how intestinal immune cells communicate with epithelialcellstoregulateresponsestoinflammatorysignals.Multivariatemodelinganalysisofalargedatasetcomposedof phospho-signals, cytokines, andimmunecellpopulations withintheintestinerevealedanintimaterelationshipbetween immunecellsandtheepithelialresponsetoTNF-a.Ablationoflymphocytesintheintestinepromptedadecreaseinthe expressionofMCP-1,whichinturnincreasedthesteadystatenumberofintestinalplasmacytoiddendriticcells(pDCs).This change in the immune compartment affected the intestinal cytokine milieu and subsequent epithelial cell signaling network,withcellsbecominghypersensitivetoTNF-a-inducedapoptosisinawaythatcouldbepredictedbymathematical modeling.Insummary,wehaveuncoveredanovelcellularnetworkthatregulatestheresponseofintestinalepithelialcells toinflammatorystimuliinaninvivosetting. Citation:LauKS,Cortez-RetamozoV,PhilipsSR,PittetMJ,LauffenburgerDA,etal.(2012)Multi-S