炎症反应Toll信号传导通路［主题词］炎症；信号传递；基因［中分类号］R364.5［文献标识码］A［］1000-4718(2000)06-0567-06TollreceptorsignalingpathwayininflammationWANGBo-yao,HUANGNing,WUQi(ResearchUnitofInfectionImmunity,DepartmentofPathophysiology,WestChinaUniversityofMedicalSciences,Chengdu610041,China)【AReview】Tollsignalingpathwaymayplayacurcialroleininductionofinflammation-associatedgeneactivation.Originally,theToll/spaetzle/Cactus-DorsalsignalingpathwayisestablishedintheDrosophilaembryonicdevelopment.Recently,theTollsignalingpathwayinadultDrosophilahasbeenestablishedintheinductionofantimicrobialpeptideexpression.FivehumanToll-likereceptorgenes(hTlrl-5)andonemouseToll-likereceptorgene(mTlr-4)havebeenisolated.TollandToll-likereceptorgenesencodedmoleculesaretransmembraneproteinswithanextracellularleucinerepeatdomainandacytoplasmicdomainhomologoustoIL-1receptors.TheintracellularsignalingcascadeinvolvesTube,Pelle,andCactus-DorsalcomplexinDrosophila,andMyD88,IRAK,TRAF6,NIK,αβ-IκBkinase,andIκB-NFκBcomplexinmammals.DorsalandNFκBaretranscriptionfactors,whileCactusandIκBaretheirinhibitors.Whentheinhibitorsphosphorylated,thenuclearfactorsarereleasedandmoveintonucleus,leadingtoimmunegeneactivation.IthasbeenshownfrominvitrosystemthatTlr-4mediatedLPSsignalinginhumanmonocytesforexpressionofIL-1,IL-6,IL-8,andcostimulatorB7-1whichprovidessecondsignalforTcellresponse.Tlr-2canalsomediateLPSsignalinginhumanmonocytes,leadingtotheproductionofproinflammatorymediators.MicrobiallipoproteinsarepotentstimulatorsofIL-12productionthroughTlr-2signalingbyhumanmacrophages,andcanstimulateTlr2-dependenttranscriptionofinduciblenitricoxidesynthaseandtheproductionofnitricoxide,apowerfulmicrobicidalpathway.FindingsofapointmutationofTlr-4inLPStolerantC3H/HeJmousestrainandadeletionofTlr-4inLPSresistantC57BL/10ScCrmiceprovideaninvivoevidencestronglysupportingthecrucialroleofTlrsinLPSmediatedinflammation.ItisproposedthattargetingTlrswoulddevelopnewremediesfortreatmentofinflammatorydisordersandforimmunotherapyofmucosalinfectionsandcancer,etc.［MeSH］Inflammation;Signaltransduction;Genes炎症反应是机体天然抵抗微生物侵袭的重要武器［1］，因此从免疫学角度讲又称之为天然免疫。补体系统、凝血系统、急性期反应蛋白、吞噬细胞、内皮细胞和上皮细胞等构成这个反应系统的主要元件。天然免疫在发生学上是有机体最古老的抗感染防御机制，它使用胚胎细胞编码的形态识别受体(patternrecognitionreceptors,PRRs)识别微生物的保守的分子成分，如LPS、胞壁脂蛋白、甘露糖和RNA病毒双链RNA等，产生抗微生物及其毒性因子的免疫反应［2］。这种分子形态识别受体从分布上可分为细胞性受体和体液性受体；从功能上可分为循环血中的体液性受体和在细胞膜上表达的内吞受体以及信号受体等。体液性受体如甘露糖结合蛋白、C反应蛋白、血清淀粉样蛋白等介导补体系统的激活和调理吞噬作用，而脂多糖结合蛋白(LBP)识别LPS，起浓集血中LPS并传递给CD14的作用，它们均属于由肝细胞合成的急性期反应蛋白；内吞受体如巨噬细胞甘露糖受体、清道夫受体和补体受体等介导吞噬作用；信号受体如CD14和Toll在细胞介导的炎症反应中起信号传导作用。天然免疫细胞识别病原体相关分子形态(pathogenassociatedmolecularpatterns,PAMs)或蛋白水解信号，一方面诱导抗菌肽的合成，直接杀伤侵入的病原微生物；另一方面诱导内源性信号的表达，如炎症预激细胞因子(TNF、IL-1等)、趋化细胞因子(IL-8、MCP、MIP等)、粘附分子、共刺激因子(B7、IL-12等)以及一氧化氮合酶(产生一氧化氮)等，以便更有效的动员机体的防御力量来抵抗病原微生物的侵入。人们已熟知髓性白细胞膜CD...