Thrombin‐induced CCN2 expression in human lung fibroblasts requires the c‐Src/JAK2/STAT3 pathway

[摘要] ThrombinisamultifunctionalserineproteaseandanimportantfibroticmediatorthatinducesCCN2expression.WepreviouslyshowedthatthrombininducesCCN2expressionviaanASK1‐dependentJNK/AP‐1pathwayinhumanlungfibroblasts.Inthisstudy,wefurtherinvestigatedtherolesofc‐Src,JAK2,andSTAT3inthrombin‐inducedCCN2expression.Thrombin‐inducedCCN2expressionandCCN2‐LucactivitywereattenuatedbyaJAKinhibitor(AG490)andJAK2DN,STAT3DN,andtheSTATdecoyODN.Moreover,transfectionofcellswithaCCN2‐mtSTAT‐Lucconstructinhibitedthrombin‐inducedCCN2‐Lucactivity.TreatmentofcellswiththrombincausedJAK2phosphorylationatTyr1007/1008andSTAT3phosphorylationatTyr705intime‐dependentmanners.Thrombin‐inducedSTAT3phosphorylationwasinhibitedbyAG490andJAK2DN.Thrombin‐inducedSTAT3bindingtotheCCN2promoterwasanalyzedbyaDNA‐bindingaffinitypull‐downassay.Inaddition,thrombin‐inducedCCN2expressionandCCN2‐Lucactivitywereinhibitedbyc‐SrcDNandPP2(anSrcinhibitor).Transfectionofcellswithc‐SrcDNalsoinhibitedthrombin‐inducedJAK2andSTAT3phosphorylation.Takentogether,theseresultsindicatethatthrombinmightactivatec‐SrctoinduceJAK2activation,whichinturn,causesSTAT3activation,andfinallyinducesCCN2expressioninhumanlungfibroblasts...

[学科分类] 生理学

[关键词] inflammation;transcription factors;gene regulation;signal transduction;lung