搜索
2015103110IMMUNOLOGICALJOURNALVol.31No.10Oct.2015，、CD34+/CD86+CD25+/CD44+/FcR+T，kupffer、、、、。，。，、，、、、，。、、。，M1，，。M2，，。，（lipopolysaccharide，LPS）（Classicallyactivatedmacrophage，CAMsorM1），4/13（interleukin4/13）（alternativelyactivatedmacrophage，AAMsorM2）[1]，M2M2a、M2bM2c3。2Th1/Th2。M1，··[]1000-8861（2015）10-0911-07；[DOI]10.13431/j.cnki.immunol.j.20150192M1/M2，，，，*[]、。（M1）（M2），。，。JAK/STAT、PI3K/Akt、C-JunN-terminalkinase（JNK）、NotchB7-H3/STAT35。、、、，。[]；；；[]R392.12[]AProgressinsignalingpathwaysofmacrophageM1/2polarizationRUANJingyao1,CHENBicheng2,ZHANGXile1,ZHANGRong1,HUANGHuanjie2,*1.FirstClinicalMedicalSchool,WenzhouMedicalUniversity,Wenzhou325000,China2.DepartmentofSurgery,FirstAffiliatedHospitalofWenzhouMedicalUniversity,Wenzhou325000,China*CorrespondingAuthor:HUANGHuanjie,E-mail:95667089@163.com[Abstract]Plasticityandinflammatoryfactor-inducedheterogeneityaremaincharacteristicsofmacrophages.Thus,differentenvironment-derivedstimulicouldinducethemacrophagephenotypicpolarization,suchasclassicallyactivatedmacrophage(M1)andalternativelyactivatedmacrophage(M2).Andthefunctionsofthetwokindsofpolarizationstatesarealmostantistaticoneachother.Macrophagepolarizationisacomplexprocess,inwhichmorethanonefactorinteractoneachotherandregulatedbyavarietyofsignalmoleculesandsignalingpathways.Hereinthisreview,weshowfivesignalingpathwayswhichhavebeenstudiedmaturelyuntilnow,suchasJAK/STAT,PI3K/Akt,C-JunN-terminalkinase(JNK),NotchandB7-H3/STAT3signalingpathway.Macrophagesaretheimportantregulatorsofthebodymetabolism,hematopoieticfunction,angiogenesis,apoptosisandtheprocessoftumorformation.Thereviewonsignalingpathwaysofmacrophagepolarizationmayprovideanewthoughttotreatmacrophage-associatedillnesses.[Keywords]Macrophagepolarization;Classicactivation;Substitutiveactivation;Signalingpathway：325000，（，，），（，）*：，E-mail：95667089@163.com911··2015103110IMMUNOLOGICALJOURNALVol.31No.10Oct.2015。M2、、。，2，。，。JAK/STAT、PI3K/Akt、C-JunN-terminalkinase（JNK）、Notch，B7-H3/STAT3M2。1M1（M0）IFN-γ、LPSM1，，IL-1、IL-6、-α（tumornecrosisfactor-α，TNF-α）、（inducedNOS，iNOS）；，-1（monocytechemotacticprotein-1，MCP-1）、CCL2-4CXCL8-11,Th1，Th1。M1MHCIICD80CD86[2]。M1、，，、T。M1，TNF-αIL-1βT（cytotoxiclymphocyte，CTL）[3]。M1，、。，M1，，[4]。2M2IL-4IL-13M2a；M2b；IL-10M2c。M2（vascularendothelialcellgrowthfactor，VEGF）、-1（Arginase-1，Arg-1）、（plateletderivedgrowthfactor，PDGF）、-β（transforminggrowthfactor,TGF-β）IL-10。M2、。。，M2CCL17、CCL18、CCL22、CCL24，Th2、、。（tumor-associatedmacrophages，TAMs）M2，（matrixmetalloproteinases，MMP），MMP-2、MMP-7、MMP-9、CCL18、CCL22，。QinRNA，（）β2M2，。B7-H3M2[5]。M2，。M2、、，[6]。M2TGF-β1BMP7，EMT-。M2EMT，。33.1JAK/STATSTATs，、、，8。（Januskinase，JAK），STAT，STAT，，。JAK/STAT，，。JAK-STAT[7-8]。，IFN-γJAK-STAT，。IFN-γSTAT1，，[9]。IFN-γM1，IFN-γ/JAK-STAT1M1。（suppressorofcytokinesignaling,SOCS）JAK/STAT，。SOCSSOCS1、SOCS2、SOCS3。SOCS3STAT3，912··2015103110IMMUNOLOGICALJOURNALVol.31No.10Oct.2015。QinSOCS3LysMCre-SOCS3fl/flSOCS3fl/fl，JAK/STAT，IL-1β、IL-6、IL-12、IL-23INOSM1,Th1Th17。Lawrence[10]IFN-α/βIFN-γ。STAT6、IRF4-γ（peroxisomeproliferator-activatedreceptor，PPAR-γ）Arg-1、Mrc-1Chil3M2。STAT6IL-4，JAK/STAT6。PPARSTAT6M2，STAT6/PPAR，[11]。Park[12]，-1-（sphingosine-1-phosphate，S1P）M2，IL-4S1PM2。S1PS1P1S1P2，（extracellularsignal-regulatedkinase，ERK）JNKp38MAPKIL-4。IL-4IL-4RαIL-2Rγ，STAT6，SOCS1SOCS3，M2。3（1）：①IL-4IL-4Rα，JAK，JAK。JAK（Insulinreceptorsubstrates，IRS），2（Growthfactorreceptorbound-2，GRB2）PI3K，STAT6，SH2STAT，STAT6，。STAT6KLF-4、PPAR-γ，M2（Jumonjidomain-containingprotein3，Jmjd3），H327，-4（interferonregulatoryfactor4，IRF-4），M2[13]。②S1PS1P1S1P2，ERKJNKp38MAPKIL-4。IL-4IL-4RαIL-2Rγ，STAT6，SOCS1SOCS3，M2。③IFN-γJAK，STAT1，M1，IFN-α/βIFN-γ，SOCS3，STAT1，M1。3.2PI3K/Akt-3-（phosphatidylinositol-3-kinase，PI3K）-3,4,5-（PIP3），。，，PI3K,、，[14]。Akt（PKB）PI3K，3/（Akt1、Akt2、Akt3），，、、[15-16]。PI3K/Akt。Akt1，Akt1（Akt1-/-）M1，Akt2-/-M2[17-18]。，Akt1（HMDMs）Mcl-1PI3K，。MiR-125a-5pM2M1，Akt1，miR-155，M2[19]。-κB（NF-κB），PI3K/Akt，M1、，，[20-21]。Li[guaninenucleotide-1JAK/STATFig1JAK/STATsignalingpathway913··2015103110IMMUNOLOGICALJOURNALVol.31No.10Oct.2015bindingprotein，G（i）]1/3LPSPI3K/Akt。Gαi1/3TLR4，NF-κB、MAPKs、IRF3，NF-κBPI3K/Akt。LPSGαi1/3，1（growthfactorassociatedbingdingprotein，Gab1）PI3Kp85，NF-κB，Akt。mTOR（mTORC1）/，、。mTORC1（TSC1TSC2）。TSC1TSC2mTORC1[22]。BylesTSC1，TSC2，mTORC1。Tsc1Δ/ΔIL-4M2，。[23]，IL-10PI3K，Akt，mTORC1，mTORC1IL-4Akt1，M2。3（2）：①、LPS、DSSHCD，，PI3K，Akt1Akt2。Akt1-/-miR-155，RelA/NF-κB[18]，(SOCS)1，M1，M1。Akt2-/-miR-155，CAAT/β（CAAT/enhancer-bindingProteinsβ，C/EBPβ），M2。，miR-342-5pAkt1miR-155，M1，iNos2[24]。TLR2，Myd88miR-342-5p。②LPSGαi1/3Gab1PI3Kp85，Akt。③Rocher[25]-7（Bonemorphogeneticprotein-7，BMP-7）BMPR2，SMAD1/5/8，PI3K，Akt1mTOR，M2。3.3JNKJNK（mitogen-activatedproteinkinases，MAPKs）。MAPKs、、。，JNKJNK1、JNK2、JNK33，，。（adiposetissuemacrophages，ATMs），TNF-αiNOSIL-6。，ATMsM2M1。JNK，[26-27]。3（mixed-lineagekinase3，MLK3）3（mitogen-activatedprotein3kinases，MAP3K）JNK。MLK3JNKM1[28]。Kruppel（Kruppel-likefactors，KLFs）、、，。Date[29]KLF-6NF-κB，M1，PPAR-γM2。（epoxyeicosatrienoicacids，EETs），，、。EETsNF-κB。DaiEETsPPAR-α/γHO-1，NF-κB，M1。2（3）：①HFDCCR2NF-κBJNK，AP-1，M1，M12PI3K/AktFig2PI3K/Aktsignalingpathway914··2015103110IMMUNOLOGICALJO