[生物医药论文精品a]肿瘤坏死因子相关凋亡诱导配体：皮肤病治疗新的药物作用靶点

1肿瘤坏死因子相关凋亡诱导配体皮肤病治疗新的药物作用靶点A1A0A2A4A3A6A5A7A9A8A10A11A12A13A15A14A11A16A17A13A18A20A21A14200433【摘要】肿瘤坏死因子相关凋亡诱导配体（TRAIL）是肿瘤坏死因子超家族成员之一，具有选择性的诱导变异细胞的凋亡，对维持机体内环境的稳定具有重要作用，由于TRAIL具有调节皮肤的增生、凋亡、炎症、免疫、维持皮肤器官内环境的稳定等特点，在皮肤疾病研究中成为热点。本文将综述TRAIL在黑色素瘤、特应性皮炎、皮肤利什曼原虫病、银屑病关节炎等皮肤疾病中的研究进展，提示TRAIL可能作为某些皮肤疾病药物治疗的新靶点。【关键词】TRAIL；皮肤；皮肤疾病；凋亡DEVELOPMENTOFTRAILRESEARCHINSKINDISEASEYANGJISHUN,HUJINHONG,LIUJIYONG,ZHUQUANGANG,LIFENGQIANDEPARTMENTOFPHARMACY,CHANGHAIHOSPITAL,SECONDMILITARYMEDICALUNIVERSITY,SHANGHAI200433,CHINA【ABSTRACT】TUMORNECROSISFACTORTNFRELATEDAPOPTOSISINDUCINGLIGAND,TRAILISONEOFMEMBERSOFTHETNFGENESUPERFAMILYTHATINDUCESAPOPTOSISOFMANYTRANSFORMEDCELLSSELECTIVELYITISIMPORTANTTOSUSTAINSTABILITYOFINTERNALENVIRONMENTTRAILISABLETOREGULATEPROLIFERATION,APOPTOSIS,INFLAMMATION,IMMUNITYETALINSKIN,WHICHHASCOMPREHENSIVESTUDYINSKINDISEASETHISPAPERWILLREVIEWTRAILDEVELOPMENTINSKINDISEASEINCLUDINGMELANOMA,AD,CUTANEOUSLEISHMANIASIS,PSORIATICARTHRITISETALITINDICATESTHATTRAILMIGHTSERVEASANEWDRUGTARGETFORSKINDISEASE【KEYWORDS】TRAILSKINSKINDISEASEAPOPTOSIS肿瘤坏死因子相关凋亡诱导配体TUMORNECROSISFACTORTNFRELATEDAPOPTOSISINDUCINGLIGAND,TRAIL，是最近发现的TNF超家族新型凋亡分子，其胞外区与FASL具有较高的同源性，它能选择性的诱导肿瘤细胞、变异细胞以及病G8614G5875G7591的细胞发生凋亡，G13792对G8503G5132细胞G8821有G7186G14891G8614性，G5194G1000TRAIL在诱导细胞凋亡G17819G12255中，具有较TNF、FASLG6164G5353G17227的炎症G2465应G7138G7186较G4581的G1260G2195，在与增生、凋亡相关的疾病中G5483G2052G5203G8879的研究，本文对TRAIL在皮肤疾病研究中的进展进G15904综述。1TRAIL及其受体A19A22A23A24A25A26A27A28A291982A30A31A32A31A33A34A31A35A36A37A38A39A40A41EMAILJASUNYANGHOTMAILCOMA42A43A19A22A23A24A25A44A45A46A291949A30A31A47A31A33A34A31A48A49A31A50A51A52A53A31A37A38A54A55A25A56A57A52A58A59EMAILHUJHSMMUEDUCN2TRAILG2460G12228为APO2LG6122TNFSF10,G13546G11733G1147物G4658于II型G17340G14192G15519G11345，G5203G8879分G5079于G14098、G13966、G13970、G13940G17959、外G2620G15892细胞及G13986G11436等G8503G5132G13464G13467。TRAILG17902G17819与靶细胞G15932G19766的G2475体G13479G2524G13792发G6393生G10714作用。G11458G2081发现的G1166G12879G6164具有的特异性TRAILG14192G2475体有5G1022，G18129G4658于I型G17340G14192G15519G11345，分G2047为死亡G2475体TRAILR1/DR4、TRAILR2/DR5G2656诱G20587G2475体TRAILR3G715DCR1、TRAILR4G715DCR2及可G9354性OPGOSTEOPROTEGERIN，其中DR4、DR5的胞内区G2559有死亡G13479G7512G3507（DEATHDOMAIN,DD）,G17902G17819诱导凋亡G1461G2507G17728导G5353发细胞凋亡。DCR1、DCR2的胞外区与DR4、DR5具有高G5242的同源G8700G3534G18252G5219G2027，G1306由于DCR1G13582G4581胞G17148内的死亡G2163能区，DCR2具有G993G4448G6984的死亡G13479G7512G3507，因G13792G1120G13785G993能G1268导细胞内的凋亡G1461G2507，G1306能与DR4、DR5G12466G1117性G13479G2524TRAIL因子，G1186G13792G6245G2058TRAIL诱导的细胞凋亡。TRAIL与G2475体G13479G2524，G1039要G17902G17819FAS相关G15519G11345死亡的G13479G7512G3507（FASASSOCIATEDPROTEINWITHDEATHDOMAIN,FADD）G1461G2507G5353G17227的CASPASE8G13435G13864G2465应凋亡G1461G2507G17728导G17902G17347、由BCL2G15519G11345家族G5353G17227的G13459G12902体G713细胞色素C凋亡G1461G2507G17728导G17902G17347以及G17902G17819NFKBG17902G17347G5353G17227的凋亡G1461G2507G17728导G17896G5464诱导细胞发生凋亡1。TRAIL凋亡作用G1039要G2475诱G20587G2475体、G7692因子（NFKB）、细胞FLICEG6245G2058G15519G11345（CFLIP）、凋亡G6245G2058G15519G11345（IAPS）、BCL2G15519G11345家族、SURVIVIN等相关物G17148的调节2。2TRAIL与皮肤疾病皮肤是G1166体最G3835的器官，是机体G2656外G11040之G19400的G3837G9994G4643G19568，由G15932皮、G11507皮G2656皮G991G13464G13467G7512成。G15932皮G1039要由G16294G17148G5430成细胞、黑色素细胞、G7403G7696G8733G7043细胞、G2656G21626G1823G4584细胞等G7512成，G17902G17819G3534G5225G14192G5114与G11507皮相G17842G6521。G11507皮G1039要由纤维、G3534G17148G2656细胞成分等G13464成。近几年来，TRAIL在皮肤增生、凋亡、炎症、免疫等疾病中的研究已成为皮肤药G10714学的研究热点。皮肤是G17819敏G2656炎症的频发部位，发病机G2058复杂，G16294G17148G5430成细胞G2656成纤维细胞等参与了G2465应，TRAIL与G16294G17148G5430成细胞的增生、分化密切相关3，在调节皮肤炎症的发生发展中具有重要的作用，维持了皮肤内环境的稳定。皮肤黑色素瘤黑色素瘤简G12228恶黑，是一G12879G17227源于神经脊黑色素细胞的恶性肿瘤，临床上G4581见，发病率占全身恶性肿瘤的12，G1306近年来有逐渐升高趋G2195，病变部位以皮肤最为多见，其发病G5132较隐匿，G993易G5353G17227患G13785的重视，一般治疗时为时已晚，G1000治疗效果欠佳。故早期诊断、及时治疗特G2047重要。TRAIL作为一种很有潜力的抗癌因子，与其G2475体G13479G2524后，诱导G3835多数肿瘤细3胞的凋亡。黑色素瘤的高发病率与药物治疗的抗药性密切相关，其耐药性与相关的凋亡G2656抗凋亡G3534因G2656G15519G11345的G15932达有关4，GILLESPIES等学G137855研究证实，G15519G11345激酶C的激活能够调节TRAIL诱导的黑色素瘤细胞的凋亡，其机G2058与G15519G11345激酶C能够调节G13459G12902体上游G2656半胱G3837冬酶8G991游的G1461G2507G17728导G17902G17347有关。KURBANOVBM等6用免疫G13464G13467化学方法证实黑色素瘤细胞对TRAIL的敏G5875性与其G15932G19766的DR4G15932达密切相关，G13792WUJJ等7认为TRAIL对黑色素瘤细胞耐G2475与P53G2656P21的G15932达的G991降G2656ERK1/2、AKTG15519G11345的激活密切相关。ZEISEE等8在对TRAIL敏G5875的G1166G12879细胞A375G2656抗TRAIL细胞株IGR37对照研究G15932G7138FLIPG15519G11345的G15932达G2475UVB的调节，在低剂量的UVB照射G991，用TRAIL处G10714的IGR37细胞的凋亡G7138G7186增加，其原因是UVB可以G6245G2058FLIPG6245G2058凋亡G15519G11345的G15932达，G1186G13792促进TRAIL诱导的细胞凋亡。其确切的药物耐G2475性原因有待进一步证实。关于TRAIL诱导变异细胞的凋亡G1461G2507G17728导G17902G17347方G19766尚存在一定的G1117议，LARRIBEREL等9用干细胞因子激活磷脂酰肌醇（G7133）激酶（PI3K）G2656ERK，发现能够强烈的保护黑色素瘤细胞免G2475TRAIL诱导的凋亡，G5430成了SCF/PI3K/AKTG13435G13864瀑G5079凋亡G17902G17347。ZHANGXD等10实验用MEKG6245G2058剂U206G6122MKK1G15519G11345的G7186性负相G15519G11345来G6245G2058ERK1/2G1461G2507，发现能G7186G14891提高对TRAIL敏G5875的色素瘤细胞发生TRAIL诱导的细胞凋亡，这与G13459G12902体的G17340G14192电位的迅速降低G2656SMAC/DIABLO向细胞G17148释放有关。这些G13479果G15932G7138ERK1/2G1461G2507G17902G17347可能阻止黑色素瘤细胞发生TRAIL诱导的凋亡。TRAIL在协同药物治疗黑色素瘤方G19766，许多学G13785也做了G3835量的研究，TRAIL能够与多种抗癌药物发生协同作用，诱导癌细胞的凋亡，提高抗癌药物的疗效11。GILLESPIES等12学G13785实验发现TRAIL能够协同G13464G15519G11345脱乙酰G3534酶G6245G2058剂SBHA杀伤色素瘤细胞，其分子机G2058是在TRAIL存在G991，SBHA能够G991调BCLXL,MCL1ANDXIAPG15519G11345的G15932达，同时上调BH3ONLYPROTEINBIMEL的G15932达。这种诱导肿瘤细胞凋亡G17896G5464可能是G17902G17819细胞的G13459G12902体凋亡G17896G5464实现的。SONGJH等13用21例黑色素瘤细胞株G2656对TRAIL敏G5875的初期黑色素瘤细胞，G9994后检测顺G19094、G1393G6188G8862G14539对TRAIL耐G2475的肿瘤细胞株诱导凋亡作用的协同效应，发现能够增强TRAILG1183导的凋亡作用，其机G2058是G6245G2058细胞内CFLIPG15519G11345的G15932达。VANOVVN等14用G15932皮细胞生G19283因子G6245G2058剂G2656G1134G11787G18252G11428综G2524治疗G1166G12879的EGFRG19463性的黑素瘤细胞，发现能够G7186G14891诱导黑色素瘤细胞的凋亡，其机G2058是G17902G17819G6245G2058PI3KAKTG1461G2507G17728导G17902G17347以及促进TRAILG1183导的细胞凋亡。G2490外IVANOVVN，HEITK15等在实验中证实G1134G11787G18252G19060能够加G5567TRAILG1183导的黑色素瘤细胞的凋亡，其凋亡机G2058为上调细胞G14192G15932G19766的TRAILR1/R2的G15932达G2656G991调CFLIPG15519G11345的G15932达。中药在4治疗黑色素瘤方G19766也G2474G5483了一定的成果，GILLESPIESK等16学G13785实验证实G5052G3835G6131G1120G14832醇能够G2464重诱导TRAILG1183导的黑色素瘤细胞的凋亡。特应性皮炎特应性皮炎AD是G17963G1268易G5875G1022体在环境因素作用G991发生的变G5589G2465应性疾病。多数患G13785以后发生G2754G2924G2656G17819敏性G21775炎，其特G5461G3355为IGEG2656外G2620G15892G2992G18252G12902细胞升高。在G8504G12879皮肤疾病中，TRAIL与其G2475体G13479G2524，激活G19762凋亡G1461G2507G17728导G17896G5464，调节皮肤炎症G2465应，G1186G13792发G6393其作用。VASSINAE等17学G13785发现在特异性皮炎患G13785的外G2620G15892T细胞G2656G2345G7692细胞中与G8503G5132G1166相G8616，TRAIL有G7186G14891G15932达。G1000抗炎作用是因为TRAIL能够诱导G11345G1183素G7131G2475体G6338抗剂（IL1RA）的G15932达。因G11345G1183素G7131与其G2475体G13479G2524后，G1147生强烈的G14280炎效应，G17902G17819IL1RA的G1147生，能阻断G11345G1183素G7131的生物学效应，G1186G13792G1955G17743炎症G2465应。WARNNISSORNP等18学G13785也发现特应性皮炎疾病中有TRAIL的G15932达。这些研究成果可能为治疗特应性皮炎的药物的研发提G1391新的作用靶点。皮肤利什曼原虫病利什曼原虫G6365其G7092G19841G8623体G4504生的脊G7906G2172物G4499G1039的G993同分为G1016G3835G12879，G2375G10240G15904G2172物利什曼原虫及G2766G1095G2172物利什曼原虫。G2081G13785对G1166体G7092G14280病作用，后G13785中有许多G4504生G1166体，其中有的G4504生于皮肤的G5052G3136细胞内，G5353G17227皮肤利什曼病（CUTANEOUSLEISHMANIASIS），G3926G11817G3835利什曼原虫（LMAJOR）G2656G3708G16211G2745利什曼原虫LMEXICANABIAGI,1953GARNHAM,1962在G6117G3281，G7472G8675是G1039要的G14280病虫种。EIDSMOL等19学G13785G18331用凋亡特定的G5506点G19465G6175G8585检测发现在利什曼原虫G3533G1871的上G9177G3824中，TRAIL的MRNAG2656G15519G11345G15932达G7186G14891增加，G1000在皮肤利什曼原虫病患G13785的皮肤G7643本中发现促凋亡G15519G11345TRAILR2的G15932达。这可能是导G14280患G13785G13464G13467G6451G4487G2656G9303G11125的原因。银屑病关节炎银屑病关节炎（PSORIATICARTHRITIS,PSA）是一种与银屑病相关的炎性关节病，具有银屑病皮G11149G5194导G14280关节G2656G2620G3272G17731G13464G13467G11152G11183、肿G13972、G2399G11183、G1737G11840G2656G17828G2172G19568G11873，部分患G13785可有G20618G20630关节炎G2656（G6122）脊G7621炎，病G12255G17813G5322、易复发、晚期可有关节强G11464，导G14280G8543G5235。银屑病患G13785G1343457发生关节炎。G6117G3281PSA患病率G13434为123G259，银屑病是一种T细胞G1183导的G5942性免疫炎症性皮肤病，以G16294G17148G5430成细胞G17819G5242增生G2656G993G4448全分化为特G5461，G11507皮中性G12902细胞G2656激活的G9119G5064细胞G9036G9082G1288G8623细G15892G12661G6209G7366、G11507皮G9195G1998G2656G15892G8981增加的G15892G12661G6925变。TRAIL作为一种G1183导细胞凋亡的一种重要的配体，在银屑病相关的治疗中具有重要的G5859G1053，HOFBAUERLC等20学G13785在一G20045研究中发现，与G8503G5132G1166G13688G15892G9177TRAILG8712G5191相G8616，银屑病关节炎中的TRAILG7186G14891升高。G12520G137855认为，这可能与银屑病中皮肤G17819G5242G15932达TRAIL及其G2475体相关，导G14280G16294G17148G5430成细胞的增生G2656分化异G5132有关，G5194G1000可能激活了NFKBG19762凋亡G1461G2507G17728导G17902G17347，导G14280炎症的发生。3展望TRAIL作为TNF超家族的重要成员，由于能够选择性的杀伤变异细胞G2656病G8614G5875G7591的细胞的凋亡，对G8503G5132细胞G3534本G7092G8614性等G1260点，成为肿瘤研究G20058G3507的热点，近几年来TRAIL在皮肤增生、炎症、免疫等相关疾病的研究中也逐渐成为热G19388，G1306G2052G11458G2081为止，有关皮肤TRAIL的研究G6265G17959G17836G8616较G19658G6967，其在皮肤增生、炎症性疾病中G6210G9448的作用及其机G2058，G1177G19764G11458G2081的研究G17836G993能做G1998确切的G6265G17959。TRAIL在G14270身免疫性疾病中的研究G3281内外研究较G4581，由于在TRAIL的G1461G2507G17728导G17902G17347方G19766研究，有关学G13785G17836存在一定的G1117议，G19668要进一步研究。G1306G19555着对TRAIL及其G1461G2507G17728导G17902G17347研究的G993断深入，其与皮肤免疫、增生、炎症等相关疾病的关系研究也日益G7138确。G18331用RNA沉默、G3534因修饰G6122敲除技术、G15519G11345G17148G13464学等研究，必将对阐G7138TRAIL在皮肤性疾病中地位发G6393重要的作用，为皮肤疾病的治疗提G1391G10714论G3534础，研究TRAIL在皮肤疾病中的研究必将有助于寻找药物作用的新靶点，对提高药物疗效、开发经皮给药G2058剂、防止药物对皮肤的G6451伤具有重要的G5859G1053。A60A61A62A63A64A65A66A67A68A69A68A70A71A72A73A74A75A76A68A77A72A78A71A79A80A81A82A83A84A85A74A86A71A79A87A88A89A68A73A72A90A91A90A78A91A73A71A73A72A79A87A72A89A78A71A92A72A78A71A91A79A91A93A94A95A96A72A90A90A72A97A82A98A88A69A99A100A78A91A96A71A79A68A94A68A78A101A67A83A102A98A88A69A91A90A68A72A79A89A100A78A91A96A71A79A68A79A68A78A101A91A69A96A75A103A104A104A105A75A104A106A107A108A109A110A105A111A102A105A82A64A112A66A99A113A72A101A114A72A102A115A72A69A96A72A69A81A75A97A72A68A115A74A75A84A68A88A95A67A75A68A78A72A114A82A76A91A101A79A69A68A116A88A114A72A78A71A91A79A91A93A97A89A114A102A117A75A95A86A74A118A91A69A74A85A118A73A106A119A74A85A118A72A79A87A73A88A69A92A71A92A71A79A108A77A100A73A71A84A94A85A73A73A68A79A73A71A78A71A120A68A73A69A68A73A71A73A78A72A79A78A70A68A114A72A79A91A70A72A89A68A114A114A73A78A91A85A90A91A117A86A121A83A84A85A74A86A102A71A79A87A88A89A68A87A72A90A91A90A78A91A73A71A73A82A99A68A114A114A76A68A72A78A113A76A71A93A93A68A69A67A83A102A99A68A114A114A87A68A72A78A113A72A79A87A87A71A93A93A68A69A68A79A78A71A72A78A71A91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