細(xì)胞因子概述

促炎細(xì)胞因子白介素IL-1是一種能激活多種免疫和炎癥細(xì)胞的前炎性細(xì)胞/IL-1包括兩種由不同基因編碼產(chǎn)17kuIL-1(p15.0).CK和炎癥遞質(zhì)的產(chǎn)生，誘發(fā)抗TB分化，介導(dǎo)免疫球蛋白的分泌，由此激活補(bǔ)體，增強(qiáng)細(xì)胞免疫和體液免疫介導(dǎo)的組織損傷過程.還能促進(jìn)血管內(nèi)皮-白細(xì)胞黏附分子的表達(dá)，趨化中性粒細(xì)胞等炎性細(xì)胞進(jìn)入mRNAUC的炎癥程度成正相關(guān)，可作為臨床上判斷疾病嚴(yán)重程度和療效的指標(biāo)[1].白介素-6(IL-6)IL-6主要由活化的巨噬細(xì)胞、淋巴細(xì)胞及上皮細(xì)胞分泌，其生物學(xué)效IL-6STAT-3而誘導(dǎo)細(xì)胞間黏附分子(ICAM-1)的極化表達(dá)，后者是在炎性腸病患者中性粒細(xì)胞-上皮細(xì)胞間相互作用中起重要作用的一種黏附顆粒.因而，在慢性腸道炎癥的發(fā)病機(jī)制中起至關(guān)重要的作用[2]IL-6在急性炎癥反應(yīng)中的作血清IL-6水平比健康成人顯著升高.1.3血清IL-6水平比健康成人顯著升高.1.3白介素-8(IL-8)IL-8是一種強(qiáng)而有力的中性粒細(xì)胞趨化和活化因子，由單核細(xì)胞、上T、TNF和外源性因子細(xì)菌多糖(LPS)的吞噬作用，對嗜堿性粒細(xì)胞和T細(xì)胞也有一定的趨化作用.TNFIL-6誘發(fā)的IL-8為代表的趨化因子所介導(dǎo)的.UC患者IL-8水平mRNA檢測可作為臨床上判斷疾病嚴(yán)重程度和療效的指標(biāo).1.4白介素-12(IL-12)IL-1240kup4035kup3570ku的雜二聚體(p70)p35TBNK細(xì)胞及單核細(xì)胞等B細(xì)胞產(chǎn)生IL-12NK細(xì)胞激活因子，能促進(jìn)CD4+Th0Th1NK和TIFN-TNF-、GM-CSFIL-8等，再通過這些遞質(zhì)發(fā)揮作用.IL-12IBDCD患者的血清有明顯升高.1.5白介素-15(IL-15)IL-15IL-2.和鏈的T細(xì)胞、B細(xì)胞、NK細(xì)胞以及上皮細(xì)胞的相應(yīng)受體，促進(jìn)這T細(xì)胞分泌TNF-IFN-.UCIL-15激活而使血清IL-15釋放增加.活動性IBD治療2wk內(nèi)表達(dá)IL-15的細(xì)胞數(shù)下降.1.6白介素-16(IL-16)IL-16是趨化因子，可由CD8+T細(xì)胞、嗜酸性粒細(xì)胞、肥大細(xì)胞、CD4CD4細(xì)胞.IL-16IL-6，TNF-，IL-15等，其具體作用機(jī)制還有待進(jìn)一步的研究.1.7白介素-17(IL-17)白介素-17Mr(20-30)×103的糖蛋白，主要由基質(zhì)細(xì)胞產(chǎn)生.IL-17T細(xì)胞誘導(dǎo)和促進(jìn)炎癥發(fā)生過程中的一種重要的可溶性因子.他可促進(jìn)中性粒細(xì)胞的發(fā)育成熟，并且刺激上皮細(xì)胞、內(nèi)皮細(xì)胞、巨噬細(xì)胞及纖維母細(xì)胞等產(chǎn)生進(jìn)中性粒細(xì)胞的發(fā)育成熟，并且刺激上皮細(xì)胞、內(nèi)皮細(xì)胞、巨噬細(xì)胞及纖維母細(xì)胞等產(chǎn)生、E2(prostaglandinE2，PGE2)等炎癥遞質(zhì)，增ICAM-1的表達(dá).另外，IL-17C3等急性期反應(yīng)蛋白的產(chǎn)生，在炎癥發(fā)生過程中起重要的調(diào)控作用.UC腸道病變部位的腸黏膜固有層單個核細(xì)胞(1amina已發(fā)現(xiàn)，已發(fā)現(xiàn)，CDIL-5mRNA的表達(dá)增多.相IL-5mRNA水平也明顯升高[8].2.3白介素-10(IL-10)IL-10又名細(xì)胞因子合成抑制因子，是典型的抗炎與免疫抑制性細(xì)T細(xì)胞發(fā)揮有效功能，在穩(wěn)定腸道黏膜內(nèi)環(huán)境中發(fā)揮重要作用.IL-10可以保護(hù)對propriamononuclearcells，LPMC)IL-6IL-8IL-6的濃+TIL-17IL-17可促度與該部位LP-CD4進(jìn)局部炎癥性細(xì)胞因子的分泌，從而導(dǎo)致局部腸道炎癥的發(fā)生.IL-l7IL-6IL-8IL-l7在腸道炎癥性細(xì)胞因子的產(chǎn)生過程中IL-17UC的一種有效的新方法.1.81.8腫瘤壞死因子-(TNF-)TNFCarswelletal1975年發(fā)現(xiàn)并命名的.根據(jù)細(xì)胞來型和TNF-.TNF-17kuT細(xì)胞產(chǎn)生.TNFR1、TNFR2兩種受體的介導(dǎo)，誘導(dǎo)主要組織相容性復(fù)合體(majorhistocompatibilitycomplex，MHC)-II類抗原在結(jié)腸上皮中的表達(dá)；還可以增強(qiáng)血管ICAM-1[3].IL-8基因的表達(dá)，及上調(diào)T細(xì)胞、嗜酸性和嗜堿性粒細(xì)胞的數(shù)目.TNF-不僅能刺激巨噬細(xì)胞、纖維母細(xì)胞、平滑肌細(xì)胞、上皮細(xì)胞和內(nèi)皮細(xì)胞分泌花生四烯酸代謝物、CK和蛋白酶，還能吞噬細(xì)胞產(chǎn)物和補(bǔ)體片段引起細(xì)胞壞死、間質(zhì)中蛋白質(zhì)破壞和水腫的發(fā)生，從而促進(jìn)胃腸細(xì)胞的組織損害.此外，TNF-IFN-改.還可誘導(dǎo)結(jié)腸上皮UC的發(fā)生.CDTNF-TNF-水平也升高(在結(jié)腸D中最高).-對了解患者的病變程度和活動度具有重要意義.TNF抗體治療能明顯減少糞便中的炎性趨化因子，改善疾病狀態(tài)[4]，目前已有成功報道[5].Th1NK細(xì)胞產(chǎn)生.他的免疫調(diào)節(jié)活性最強(qiáng)，抗病毒MHC-II類抗原，使上ICAM-1增加，促進(jìn)TBNK細(xì)胞和血管內(nèi)皮細(xì)胞，促進(jìn)炎癥的發(fā)生.IFN-Th1NK細(xì)胞產(chǎn)生.他的免疫調(diào)節(jié)活性最強(qiáng)，抗病毒MHC-II類抗原，使上ICAM-1增加，促進(jìn)TBNK細(xì)胞和血管內(nèi)皮細(xì)胞，促進(jìn)炎癥的發(fā)生.IFN-BIFN-.有報道，IFN-能下調(diào)IBD患者局部IL-8的分泌[6].1.101.10單核細(xì)胞化學(xué)趨化蛋白-1(MCP-1)MCP-1是一種化學(xué)趨化因子，M13000-15000，r.MCP-1UC患者不但表面上皮有MCP-1蛋白存在，而且黏膜固有層上多種細(xì)胞中均存在此種蛋白，炎癥局部腸黏膜MCP-1mRNA表達(dá)增加抗炎細(xì)胞因子2.1抗炎細(xì)胞因子2.1白介素-4(IL-4)IL-4、、IL-8TNF-產(chǎn)生，并抑制淋巴細(xì)胞和巨噬細(xì)胞產(chǎn)生和移動，抑制超氧化物陰離子形.PGE2，.C患者的44IL-4UC2.2白介素-5(IL-5)IL-5Th2細(xì)胞產(chǎn)生，是一種最強(qiáng)的嗜酸性粒細(xì)胞趨化因子，作B淋巴細(xì)胞、TB細(xì)胞的增生和分化.IL-5IL-2IL-2IFN-的產(chǎn)生，進(jìn)而阻止炎癥的發(fā)生，故結(jié)腸T以及TNF-mRNA的水平有所下降.TGF-陽性細(xì)胞含量在計數(shù)時可以忽略不計.有報道，腺病毒載體編碼的IL-10的基因治療策略可能是一種有效的治療CD的方法[15].2.4白介素-13(IL-13)IL-13Th2IL-4有相似之憶淋巴細(xì)胞，保持Th1細(xì)胞的記憶反應(yīng)，在宿主抵御外來菌侵襲中起重要作用[24].3.4趨化因子(chemokinebCCL20，CCR6CCR6/CCL20軸在體內(nèi)腸道免疫方面的作用不可忽視[25].IL-6IBD有抑制作用的淋巴細(xì)胞，且可以抑制由其介導(dǎo)的宿主自發(fā)免疫反應(yīng)，在中斷致癌作用方面也有重要意義[9-10].已知，IL-10缺失Th1T細(xì)胞介導(dǎo)的類似于CD的結(jié)腸炎IL-10CD的復(fù)發(fā)密切相關(guān).UC患者TIL-10mRNA水平呈顯著性提高，IL-10陽性細(xì)胞在結(jié)腸中出現(xiàn)的頻率也明顯增高.即使是在非炎性IL-10mRNA水平也有所提高[13-14].IL-10Th1細(xì)胞因處，處，IL-13IL-4一樣抑制單核細(xì)胞分泌前炎性遞質(zhì)和下調(diào)有細(xì)胞毒性的單核細(xì)胞功能，但TBNK細(xì)胞的功能亦不同.IL-13能上調(diào)單核細(xì)胞呈遞抗原的能力.IBDIL-13的抗炎能力下降.UCIL-13含量的報道，結(jié)果不一[16-17].2.5轉(zhuǎn)化生長因子(transforminggrowthfactor，TGF)TGF-可以抑制胃腸道炎癥反應(yīng)[10][10]CDLPMCTGF-1UC患者則正好相反，這一現(xiàn)象可能ThTGF-1在兩組患者中的絕對或相對缺乏有關(guān)[18].另有發(fā)現(xiàn)，成纖維細(xì)胞可能通過血管內(nèi)皮生長因子的過度表達(dá)在CDTGF-的刺激成正比[19].6表皮生長因子lh)F是有3個氨基酸的單鏈多肽，DNA、RNA和蛋白質(zhì)的含量，刺激組織的生長和修復(fù)，具有保護(hù)胃腸黏膜的作用.EGF能明顯減輕結(jié)腸的潰瘍和炎癥，且明顯減低結(jié)腸組織中髓過氧化EGF可通過其黏膜的保護(hù)機(jī)制減輕UC的黏膜損傷和炎癥[20].其他具有免疫調(diào)節(jié)活性的細(xì)胞因子其他具有免疫調(diào)節(jié)活性的細(xì)胞因子白介素-7(IL-7)IL-7是淋巴細(xì)胞發(fā)展中不可缺少的細(xì)胞因子，但其在外周非淋巴組織中的作用尚不清楚.IL-7受體的IL-7/IL-7R[21].白介素-18(IL-18)IL-18IFN-誘導(dǎo)因子(IGIF)，由活化的巨噬細(xì)胞等產(chǎn)生.IL-1819235個氨基酸的罕見先導(dǎo)肽序列，無N-IL-18的前體必須與轉(zhuǎn)換酶(ICE).TNKIFN-的合成[22]，減少IL-10的含量，在CD的發(fā)病中起調(diào)節(jié)作用[23].3.3白介素-23(IL-23)CD+記4[5][5].IBD免疫發(fā)病過程中起重要作用.IL-10TNFIBD.IBD免疫發(fā)病過程中，各細(xì)胞因子的具體作用及相互聯(lián)系，以及關(guān)于細(xì)胞因子的具體治療方案，尚待進(jìn)一步研究.1 GanH,Ouyang1 GanH,OuyangQ,JiaD,XiaQ.Activationofnuclearfactor-kappaBanditsrelationship參考文獻(xiàn)消化雜志2003;11:1524-15278 SawaOshitaniN,AdachiK,HiguchiK,MatsumotoArakawaComprehensivewithcytokinegeneexpressioninwithcytokinegeneexpressionincolonicmucosaofulcerativecolitispatients.ZhonghuaNeikeZazhi2002;41:252-255colonicmucosaofulcerativecolitispatients.ZhonghuaNeikeZazhi2002;41:252-25522 g,a,s,z,n,n.6saBactivationintheintestinalactivationintheintestinalepithelia.JImmunol2003;171:3194-3201epithelia.JImmunol2003;171:3194-32013 Szlosarek3 SzlosarekBalkwillFR.Tumournecrosisfactoralpha:apotentialtargetforthetherapyofsolidtumours.Lancettherapyofsolidtumours.LancetOncol2003;4:565-573Oncol2003;4:565-5734 Scheinin4 ScheininButlerDM,SalwayScallonB,FeldmannM.Validationoftheinterleukin-10knockoutmousemodelofknockoutmousemodelofcolitis:antitumournecrosisfactor-antibodiessuppresstheprogressionofcolitis.Clincolitis:antitumournecrosisfactor-antibodiessuppresstheprogressionofcolitis.ClinExpImmunolExpImmunol2003;133:38-435 Hibi5 HibiInoueN,OgataH,NaganumaM.Introductionandoverview:recentadvancesintheimmunotherapyoftheimmunotherapyofinflammatoryboweldisease.JGastroenterol2003;38(Suppl15):36-42inflammatoryboweldisease.JGastroenterol2003;38(Suppl15):36-426 SchlottmannK,WachsFP,GrossmannJ,VoglD,MaendelM,FalkW,Scholmerich6 SchlottmannK,WachsFP,GrossmannJ,VoglD,MaendelM,FalkW,ScholmerichJ,AndusT,RoglerG.InterferonAndusT,RoglerG.InterferongammadownregulatesIL-8productioninprimaryhumancolonicepithelialcellsgammadownregulatesIL-8productioninprimaryhumancolonicepithelialcellswithoutinductionofapoptosis.IntJwithoutinductionofapoptosis.IntJColorectalDisColorectalDis2004;19:421-4297 崔海宏陳村龍楊玉捷張祚建張耀東崔耀升Thl/Th2類細(xì)胞因子-mRNA的表達(dá)世界華人analysisofintestinalcytokineanalysisofintestinalcytokinemessengermessengerRNAprofilebyreal-timequantitativepolymerasechainreactioninpatientswithinflammatorybowelwithinflammatoryboweldisease.IntJMolMed2003;11:175-179disease.IntJMolMed2003;11:175-1799 Erdman9 ErdmanSE,RaoPoutahidisIhrigMM,GeZ,FengTomczakM,RogersAB,HorwitzBH,FoxJG.CD4(+)CD25(+)HorwitzBH,FoxJG.CD4(+)CD25(+)regulatoryregulatorylymphocytesrequireinterleukin10tointerruptcoloncarcinogenesisinmice.CancerResCancerRes2003;63:6042-60502003;63:6042-60500s,e,s,y,y,y.ntyeCD4+CD8alphaalphaTcellsCD4+CD8alphaalphaTcellsintheintestinalepitheliallayerinthepreventionofinflammatoryboweldisease.Procintheintestinalepitheliallayerinthepreventionofinflammatoryboweldisease.ProcNatlAcadSciUSANatlAcadSciUSA2003;100:5324-53292003;100:5324-532911FroicuM,WeaverV,WynnTA,McDowellMA,WelshJE,CantornaMT.Acrucialrolefor11FroicuM,WeaverV,WynnTA,McDowellMA,WelshJE,CantornaMT.AcrucialroleforthevitaminDreceptorinthevitaminDreceptorinexperimentalinflammatoryboweldiseases.MolEndocrinol2003;17:2386-2392experimentalinflammatoryboweldiseases.MolEndocrinol2003;17:2386-23921212LindsayJO,CiesielskiCJ,ScheininBrennanFM,HodgsonHJ.Localdeliveryofinterleukin10inducescolonicinterleukin10productionandistherapeuticformurineadenoviralvectorsencodingmurineinterleukin10inducescolonicinterleukin10productionandistherapeuticformurineadenoviralvectorsencodingmurinecolitis.Gutcolitis.Gut2003;52:981-98713MelgarS,YeungMM,BasA,ForsbergG,SuhrO,ObergA,HammarstromS,Danielsson13MelgarS,YeungMM,BasA,ForsbergG,SuhrO,ObergA,HammarstromS,DanielssonA,HammarstromML.A,HammarstromML.Over-expressionofinterleukin10inmucosalTcellsofpatientswithactiveulcerativeOver-expressionofinterleukin10inmucosalTcellsofpatientswithactiveulcerativecolitis.ClinExpImmunolcolitis.ClinExpImmunol2003;134:127-1372003;134:127-13714SasakiM,JordanP,HoughtonJ,MengX,ItohM,JohT,AlexanderJS.Transfectionof14SasakiM,JordanP,HoughtonJ,MengX,ItohM,JohT,AlexanderJS.TransfectionofIL-10expressionvectorsintoIL-10expressionvectorsintoendothelial cultures attenuates alpha4beta7-dependent lymphocyte adhesionendothelial cultures attenuates alpha4beta7-dependent lymphocyte adhesionmediatedbyMAdCAM-1.BMCmediatedbyMAdCAM-1.BMCGastroenterol2003;3:3Gastroenterol2003;3:315LindsayJO,SandisonA,CohenP,BrennanFM,HodgsonHJ.IL-10genetherapyis15LindsayJO,SandisonA,CohenP,BrennanFM,HodgsonHJ.IL-10genetherapyistherapeuticfordextransodiumtherapeuticfordextransodiumsulfate-inducedmurinecolitis.DigDisSci2004;49:1327-1334sulfate-inducedmurinecolitis.DigDisSci2004;49:1327-133416KadivarK,RuchelliED,MarkowitzJE,DefeliceML,StrogatzML,KanzariaMM,Reddy16KadivarK,RuchelliED,MarkowitzJE,DefeliceML,StrogatzML,KanzariaMM,ReddyBaldassanoRN,vonAllmenD,BaldassanoRN,vonAllmenD,BrownKA.Intestinalinterleukin-13inpediatricinflammatoryboweldiseasepatients.BrownKA.Intestinalinterleukin-13inpediatricinflammatoryboweldiseasepatients.InflammBowelDisInflammBowelDis2004;10:593-5982004;10:593-59817FussIJ,Heller17FussIJ,HellerBoirivantM,LeonF,YoshidaM,Fichtner-FeiglS,YangZ,ExleyM,KitaniA,BlumbergRS,MannonP,KitaniA,BlumbergRS,MannonP,StroberStroberW.NonclassicalCD1d-restrictedNKTcellsthatproduceIL-13characterizeanatypicalTh2responseinatypicalTh2responseinulcerativecolitis.JClinInvest2004;113:1490-1497ulcerativecolitis.JClinInvest2004;113:1490-149718DelZottoB,MumoloG,PronioAM,MontesaniC,TersigniR,BoirivantM.TGF-beta118DelZottoB,MumoloG,PronioAM,MontesaniC,TersigniR,BoirivantM.TGF-beta1productionininflammatorybowelproductionininflammatoryboweldisease:disease:differingproductionpatternsinCrohn’sdiseaseulcerativecolitis.ClinExpImmunolImmunol2003;134:120-12619BeddyD,WatsonRW,FitzpatrickJM,O’ConnellPR.Increasedvascularendothelial19BeddyD,WatsonRW,FitzpatrickJM,O’ConnellPR.Increasedvascularendothelialgrowthfactorproductioningrowthfactorproductioninfibroblasts isolated from strictures in patients with Crohn’s disease. Br Jfibroblasts isolated from strictures in patients with Crohn’s disease. Br JSurgSurg2004;91:72-7720Procaccino20ProcaccinoReinshagenM,HoffmannZeehJM,LakshmananJ,McRobertsJA,PatelA,FrenchS,EysseleinVE.A,FrenchS,EysseleinVE.ProtectiveProtectiveeffectofepidermalgrowthfactorinanexperimentalmodelofcolitisinrats.GastroenterologyGastroenterology1994;107:12-171994;107:12-1721WatanabeM,YamazakiM,KanaiT.MucosalTcellsasatargetfortreatmentofIBD.J21WatanabeM,YamazakiM,KanaiT.MucosalTcellsasatargetfortreatmentofIBD.JGastroenterolGastroenterol2003;38(Suppl15):48-502003;38(Suppl15):48-5022LoherF,BauerC,LandauerN,SchmallK,SiegmundB,LehrHA,DauerM,22LoherF,BauerC,LandauerN,SchmallK,SiegmundB,LehrHA,DauerM,SchoenhartingM,EndresS,EiglerA.TheSchoenhartingM,EndresS,EiglerA.Theinterleukin-1beta-convertingenzymeinhibitorpralnacasanreducesdextransulfateinterleukin-1beta-convertingenzymeinhibitorpralnacasanreducesdextransulfatesodium-induce