07细胞因子及其受体

11细胞因子及其受体CytokineandcytokinereceptorsHistoryfortheresearchofthecytokines

In1957，Interferon（IFN)wasfound

In1969，termedlymphokine

In1974，denominatedcytokine

cytokinology；

internationalcytokinesociety

《Cytokine》

Companiesfordevelopingcytokinesinmanycountries

Cytockinesarelow-molecular-weightregulatoryproteinsorglycoproteinssecretedbywhitebloodcellsandvariouscells(vascularendothelialcell,epidermiccellandfibroblast)inbodyinresponsetoanumberofstimuli.

Cytokine

由免疫细胞和某些非免疫细胞（如血管内皮细胞、表皮细胞和成纤维细胞等)经刺激而合成分泌的一类小分子量可溶性糖蛋白或蛋白多肽。

细胞因子(cytokine)CytokinegeneInducingstimulusCytokine-producingcellCytokineGeneactivationReceptorsignalBiologicaleffectsOverviewoftheinductionandfunctionofCytokine

生物学效应:免疫细胞之间的信息交换及相互调节依赖于细胞因子。细胞因子除了介导、调节局部和全身免疫应答和炎症反应过程之外，还对伤口愈合、造血干细胞再生与分化密切相关。

-S-S--S-S--S-S-CC

CCC1C3C2C1C3C2C1C3C2C1C3C2G蛋白细胞因子受体Biologicaleffects:Regulationandtransferoftheinformationbetweentheimmunecells;Mediationandregulationoftheimmuneresponseandinflammation;Relationshipwiththewoundhealing,theregenerationanddifferentiationofthehemopoieticstemcells-S-S--S-S--S-S-CC

CCC1C3C2C1C3C2C1C3C2C1C3C2G蛋白cytokinereceptorsBiologicaleffectsofthecytokinesAnti-infectionandantitumorImmuneregulationapoptosisStimulatingtheproliferationanddifferentiationofhemopoieticstemcellsPromotethegrowthanddifferentiationofvariouscellsParticipationandregulationoftheinflammatoryresponsesCytokineabnormalitiesinthepathogenesisincertaindiseasesParticipationofthenever--endocrine-immunitynet细胞因子的主要生物学效应抗感染和抗肿瘤作用免疫调节作用参与细胞凋亡刺激造血细胞增埴分化促进各种细胞的生长和分化参与和调节炎症反应细胞异常可导致疾病的发生参与神经-内分泌-免疫网络参与免疫应答与免疫调节

免疫应答识别（感应）阶段 IFN刺激APCMHC-II的表达 IL-1辅助T细胞活化 IL-10抑制抗原递呈免疫应答细胞扩增阶段 IL-2、IL-4、IL-5.IL-6等促进T、B细胞的增殖与分化 TGF-b抑制淋巴细胞增殖参与神经-内分泌-免疫网络

细胞因子对神经内分泌：IL-1.IL-6、TNF等直接参与神经系统的正常发育和损伤修复 IL-1.TNF、IFN-g、PAF等诱导垂体释放ACTH，进而促进肾上腺皮质激素的释放

应激时儿茶酚氨和糖皮质类固醇分泌增多，进而抑制IL-1.TNF的合成。

在免疫应答过程中，免疫细胞之间通过细胞因子相互刺激、彼此约束，对免疫应答进行调节，维持免疫系统的稳态平衡。

1.白细胞介素(interleukin,IL)2.集落刺激因子(colonystimulatingfactor,CSF).3.干扰素(interferon,IFN)4.肿瘤坏死因子(tumornecrosisfactor,TNF)5.趋化因子(chemokine)6.生长因子(growthfactor,GF)细胞因子的种类Interleukin,ILinterleukinsaresecretedbysomeleukocytesandactuponotherleukocytes,IL-1~IL-23havebeenidentified.Colonystimulatingfactor,CSFThecytokinesthatstimulate

hemopoieticcellstoformcellcolony,Participatehemopoietic

functionarecalledCSF,forexampleGM-CSF,G-CSF,M-CSF,Epo,Tpo,GM-CSF

具有干细胞集落刺激活性的细胞因子

主要产生细胞作

用SCF纤维母细胞,肝细胞,内皮细胞,上皮细胞,基质细胞所有类型的造血干细胞,黑色素细胞,肥大细胞IL-3T细胞中性粒细胞,单核细胞,红细胞,嗜碱性粒细胞IL-5T细胞嗜酸性粒细胞IL-11基质细胞,纤维母细胞所有类型的造血干细胞,血小板GM-CSFT细胞,单核细胞,内皮细胞,纤维母细胞中性粒细胞,单核细胞,嗜酸性粒细胞,树突细胞G-CSF单核细胞,纤维母细胞,中性粒细胞M-CSF单核细胞,淋巴细胞,纤维母细胞,内皮细胞,上皮细胞单核细胞,胎盘滋养细胞EPO肾脏细胞红细胞TPO肾,肝血小板集落刺激因子的作用Interferon,IFNthecytokinesthatresistviralinfection,andinterfereviralreplication,includingIFN

,IFN

(typeI);IFN

(typeII)Tumornecrosisfactor,TNFthecytokinesthatinducedirectlyapoptosisoftumorcells,includingTNF

,TNF

(Lymphotoxin,T),FASL,CD70L,CD30L,CD40L,OX40L,TRAIL(TNFrelatedapoptosis-inducingligandGrowthfactorthecytokinesthatpromotegrowthofvariouscells,epidermalgrowthfactor,insulin-likegrowthfactor,vascularendothelialgrowthfactorChemokinechemokines,agroupoflow-molecular-weightcytokinwsincludinginterleuki8,thataffectchemotaxisandotheraspectsofleukocytebehavior.Chemokinecausesthecellularmorphologicalteration11-1mainpropertiesofthecytokinesautocrineendocrineCirculationBindingtotargetcellsindistantpartsofthebody.paracrineBindingtoreceptorsonatargetcellincloseproximitytotheproducercells1.actionmannersBindtoreceptorsonthemembraneofthesamecellthatsecretedit肥大细胞胸腺细胞BIL-4活化、增殖、分化增殖增殖

2.多效性pleiotropyIL-2、IL-4.IL-5IL-4+IL-5B细胞IL-4IFN-

5.拮抗性antagonism

3.重叠性redundancy4.协同性synergy均有刺激B细胞增殖的功能更有效地诱导IgE类别转换IL-4阻断IFN-

诱导类别转化的作用BBBOnstimulation,rapidsynthesis,release,actionanddegragation.6.rapidity7.highpotencyInfinitesimalcytokinesperformremarkablebiologicaleffects(pM,10-12M).

细胞因子受体免疫球蛋白超家族（IgsF)造血细胞因子受体超家族（HCKRsF)趋化因子受体超家族（ChRsF)TFN受体超家族（TNFRsF)IFN受体家族

Solublecytokinereceptors(sCKR)Producingmatter:

Mostofthembreakofffromthememberreceptors

SecretereceptorIL-1IL-6IL-12和IL-18TNF11-2Thecytokinesproducedbymacrophages1.activatingTcells2.stimulatingproliferationofBcellandantibodysecreting3.inducingacutephaseresponseofliver4.inducingmacrophageactivation5.trigginginflammationandfever6.stimulatingregenerationofhemopoieticstemcellsThefunctionsofIL-1MjmacrophageIL-1TNF-a157aatumornecrosisfactor,TNFTwotypes:TNF-a

TNF-b(lymphotoxin-a,LT-a)TNF-b=LTa171aaActivatedmacrophageHomology28%SamereceptorsSamebioactivitiesActivatedTcellIL-2IL-4

g-IFNUp-regulationofthecytokineproduction(IL-2,IL-4,g–IFN,CSF)andexpressionofIL-2receptorTNF-aBonemarrowInducingdifferentiationup-regulationofantibodyproductionUp-regulationofproductionprostaglandinandcytokines(IL-1,IL-6,IL-8,GM-CSF)ChemotaxisandactivationofneutrophilStimulatingproductionofCSFUp-regulationofhemopoiesis

BioactivitiesofTNF-aBcellneutrophilMjmacrophageTcell11-3cytokineproducedbyTcellsIL-2IFN-gIL-4IL-5IL-10Th1+IL-2+IL-4IL-2

IFN-g抑制IL-4IL-10细胞免疫体液免疫Th0Th2Th1和Th2细胞的分化

Th1-Th2分泌细胞因子的相互调节及其效应B细胞IgG2aTc

细胞活化巨噬细胞活化B细胞IgM,IgG1,IgA,IgE肥大细胞生长嗜酸性粒细胞生长与分化B细胞,巨噬细胞Th2细胞,肥大细胞IL-12IL-4IL-10IFN-gTh1IFN-gIL-12IL-4,IL-110,IL-13IL-2IFN-gIL-2IFN-gTNF-bIL-12IL-3IL-4Th2IL-10IL-5IL-4IL-5IL-6IL-13activated

Th1cellNKcellIL-2Promotingproliferationanddifferentiationofcells,andsynthesisofIg

PromotingproliferationandproductionofcytokinesActivated（LAK）ActivatedTcellBcellMacrophageNKcellInhibitionofcytotoxicity,promotingsecretionofIL-1ImmunebioactivitiesofIL-2NKIL-1g-IFNIL-4IL-5IL-6Th1Th1APCMjMj呈递抗原抗原活化T细胞（IL-2产生的前体细胞)Th1Th1LAK

增殖分化并分泌抗体Th1Th1B抗原刺激分化复制IL-2反应细胞

（TH或TC细胞)IL-2的生物学作用NKIL-1g-IFNIL-4IL-5IL-6Th1Th1APCMjMjAntigenpresentationantigenActivationofTcell(precursorproducingIL-2)Th1Th1LAKproliferation,differentiationSecretionofantibodyTh1Th1BantigendifferentiationreplicationIL-2reactivecells（ThorTC)ImmunebioactivitiesofIL-2TypeIinterferon:IFN-

,IFN-

anti-virusTypeIIinterferon:IFN-,immuneregulationinterferon,IFNCD8+Tcell,CD4+Tcell,NKcellVirus-infectedcellsImmunebiologicaleffectsofIFN-

Activated

Th1cellNKcellPromotingexpressionofMHC-IIandFc

,antimicroorganismandantitumor,synthesisof

TNF-

，macrophageBcellVirusinfectedcellTcellpromoting

IL-2productionIL-2RexpressionEnhancingIVhypersensitivityPlantationrejectioncytotoxicityIFN-

PromotingproductionofIgG3andIgG2aInhibitingexpressionofCD23andproductionofIgEPromotingActivationkilledNKcellInhibitingViralreplication,proliferation11-4Cytokineandclinicalapplicationrelateddiseases:deficiencyofcytokinesandreceptorsoverexpressionofcytokineshighleverofsolublecytokinereceptorsTherapeuticuseofcytokinesandtheirreceptors:supplyandadditionblockageandantagonistCommondiseasesInfectiousdiseasestumorPlantationrejectionhematocytopeniahypersensitivityAutoimmunediseases细胞因子引起的病理反应细胞因子病理反应拮抗剂适应症IL-1发热,炎症,休克,低血压,

-胰岛细胞毒性炎症性疾病,休克,类风湿关节炎,糖尿病,白血病等IL-2发热,渗漏综合征,贫血,低血压移植排斥,自身免疫病IL-3发热,流感样症状,刺激肥大细胞和嗜硷性粒细胞,刺激白血病细胞

IL-4发热,促进IgE产生,I型变态反应哮喘等I型变态反应IL-6发热,炎症,刺激骨髓瘤细胞骨髓瘤,炎症性疾病IL-8炎症炎症性疾病IL-9哮喘哮喘GM-CSF发热,流感样症状,刺激白血病细胞白血病TNF

发热,炎症,恶液质,休克休克,炎症性疾病,恶液质,类风湿关节炎IFN

发热,流感样症状,炎症炎症性疾病TPO骨髓纤维化，微血栓形成

EGF刺激某些肿瘤细胞增殖肿瘤bFGF刺激某些肿瘤增殖、转移肿瘤大剂量TNF

注射造成恶液质的小鼠模型细胞因子与临床治疗细胞因子抑制剂的临床应用

可溶性TNF受体治疗类风湿关节炎IL-1受体拮抗剂（IL-1ra)治疗类风湿关节炎DAB389-IL-2免疫毒素治疗T细胞淋巴瘤

抗TNF抗体治疗肠道自身免疫炎症细胞因子抑制剂

用于治疗炎症,自身免疫病,移植排斥,休克进入临床实验的细胞因子抑制剂名称公司适应症临床阶段可溶性IL-1受体(干粉吸入剂)Immunex哮喘I/II期可溶性IL-1受体（注射剂）

急性髓样白血病I期IL-1受体拮抗剂Amegen败血性休克(试验中止),类风湿关节炎完成III期可溶性IL-4受体Immunex哮喘I/II期抗IL-4人源化抗体SmithKline哮喘I/II期抗IL-5人源化抗体SmithKline哮喘II期可溶性TNF受体II-Fc融合蛋白Immunex类风湿关节炎，慢性心衰上市，I期可溶性TNF受体I-Fc融合蛋白Hoffmann-LaRoch休克,类风湿关节炎,多发性硬化症II/III期抗TNF

单抗（infliximab）CentocorCrohn'sDisease上市人源化抗HER2(EGFR2)单抗Genentech乳腺癌转移上市DAB389-IL-2(IL-2免疫毒素)SeragenT细胞淋巴瘤I型糖尿病,严重类风湿关节炎,牛皮癣,HIV感染上市

I/II期DAB389-EGFSeragen肿瘤I/II期人源化抗VEGF单抗GenentechInc.晚期肺癌，肠癌III期抗VEGFR2（KDR）嵌合抗体AlbertLoBuglio转移性肠癌I期人源化抗IL-8抗体（ABX-IL8）AbgenixSeverepsoriasisI/II期临床IL13-PE38QQR（IL-13免疫毒素）NeoPharm,Inc肾癌I期临床TNF

反义寡核苷酸Isis类风湿关节炎，牛皮癣I期临床抗eotaxin抗体（CAT-213）CambridgeAntibody变态反应I期临床

已批准上市的细胞因子基因工程药物名称适应症IFNα白血病、Kaposi肉瘤、肝炎、癌症、AIDSIFNγ慢性肉芽肿、生殖器疣、过敏性皮炎、感染性疾病、类风湿关节炎G-CSF自身骨髓移植、化疗导致的粒细胞减少症、AIDS、白血病、再生障碍性贫血GM-CSF自身骨髓移植、化疗导致的血细胞减少症、AIDS、再生障碍性贫血、Epo慢性肾衰导致的贫血、癌症或癌症化疗导致的贫血、失血后贫血IL-2癌症、免疫缺陷、疫苗佐剂IFNβ多发性硬化症IL-11放化疗所致血小板减少症干细胞因子(SCF)与G-CSF联合应用于外周血干细胞移植EGF外用药治疗烧伤、溃疡bFGF外用药治疗烧伤、外周神经炎

正进行临床试验的细胞因子基因工程药物细胞因子名称适应症公司IL-10炎症,银屑病,Crohn’s

病,类风湿关节炎Immunex，Schering-PloughIL-12肿瘤，