Differential Role of gp130-Dependent STAT and Ras Signalling for Haematopoiesis Following Bone-Marrow Transplantation 英文参考文献.docVIP

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Differential Role of gp130-Dependent STAT and Ras Signalling for Haematopoiesis Following Bone-Marrow Transplantation 英文参考文献.doc

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Differential Role of gp130-Dependent STAT and Ras Signalling for Haematopoiesis Following Bone-Marrow Transplantation 英文参考文献

DifferentialRoleofgp130-DependentSTATandRas SignallingforHaematopoiesisFollowingBone-Marrow Transplantation DanielaC.Kroy1,LisaHebing1,LeifE.Sander1,4,NikolausGassler2,StephanieErschfeld1,SaraSackett1, OliverGalm3,ChristianTrautwein1,KonradL.Streetz1* 1Department of Medicine III, University Hospital Aachen, Aachen, Germany, 2Institute of Pathology, University Hospital Aachen, Aachen, Germany, 3Department of Medicine IV, University Hospital Aachen, Aachen, Germany, 4Department of Infectious Diseases and Pulmonary Medicine, Charite′ University Hospital Berlin, Berlin, Germany Abstract Introduction:Bonemarrowtransplantation(BMT)isacomplexprocessregulatedbydifferentcytokinesandgrowthfactors. The pleiotropic cytokine IL-6 (Interleukin-6) and related cytokines of the same family acting on the common signal transducergp130areknowntoplayakeyroleinbonemarrow(BM)engraftment.Incontrast,theexactsignallingevents thatcontrolIL-6/gp130-drivenhaematopoieticstemcelldevelopmentduringBMTremainunresolved. Methods:Conditionalgp130knockoutandknockinmicewereusedtodeletegp130expression(gp130DMx),ortoselectively disruptgp130-dependentRas(gp130DMxRas)orSTATsignalling(gp130DMxSTAT)inBMcells.BMderivedfromtherespective strainswastransplantedintoirradiatedwildtypehostsandrepopulationofvarioushaematopoieticlineageswasmonitored byflowcytometry. Results: BM derived from gp130 deficient donor mice (gp130DMx) displayed a delayed engraftment, as evidenced by reduced total white blood cells (WBC), marked thrombocytopenia and anaemia in the early phase after BMT. Lineage analysisunravelledarestricteddevelopmentofCD4(+)andCD8(+)T-cells,CD19(+)B-cellsandCD11b(+)myeloidcellsafter transplantationofgp130-deficientBMgrafts.Tofurtherdelineatethetwomajorgp130-inducedsignallingcascades,Ras- MAPKandSTAT1/3-signallingrespectively,weusedgp130DMxRas andgp130DMxSTAT donorBM.BMTofgp130DMxSTAT cells significantly impaired engraftment of CD4(+), CD8(+), CD19(+) and CD11b(+) cells, whereas gp130DMxRas BM displayed a