乙型轉化生長因子-β
乙型转化生长因子(Transforming Growth Factor Beta, TGF-β)
是存在于‘每个人体内的免疫调节因子’,帮助改善过敏体质、调节免疫系统正常发展。
TGF-β有三种异构物,其中‘TGF-β2’是近年热门研究议题,其调节免疫的四大关键作用:
1. 减少发炎现象:透过调节型T细胞,帮助免疫系统平衡,减少发炎物质。
2. 降低过敏反应:减少IgE(免疫球蛋白E)所引起的过敏指数,降低人体的过度敏感。
3. 提升食物耐受性:帮助人体建立耐受性,减缓食物中外来蛋白质造成人体过敏的机率。
4. 抵抗病毒、细菌入侵:促进IgA(免疫球蛋白A)分泌,帮助肠道粘膜发展,抵抗外来物质侵害。
5. 避免遭受A型流感病毒H1N1感染,及减少严重度、缩短病程。
人体TGF-β2的含量多寡与免疫系统平衡高度相关
常见的遗传性过敏疾病,如:异位性皮肤炎、气喘、过敏性鼻炎等,体内均‘缺少TGF-β2免疫调节因子’
根据国际期刊发表,长期补充TGF-β2可增加体内浓度,改善体质、减少发炎、减缓过敏指数、修复组织、延长母乳对婴幼童的保护力,提升身体对食物耐受性、维持消化道机能,是婴幼儿及成人免疫系统健康的重要来源。除此之外,TGF-β2参与其他疾病的机转,包括抗肾脏纤维化、促进伤口愈合、改善干癣、干燥症、红斑性狼疮、全身性硬化症、多发性硬化症、类风湿性关节炎等自体免疫疾病[1]。
人体临床案例中,即有患者藉长期补充TGF-β2逐渐降低类固醇使用量,并获得病情改善等情况,由于安全性非常高,至今TGF-β2已广泛被应用于小儿及成人过敏免疫风湿科的临床案例。
母乳含有TGF-β2,帮助孩童免疫系统健全发展
从演化上推论,人类会将符合孩童成长需求的营养保留在母乳里,从国际研究发现,母乳中也含有TGF-β2,能帮助免疫系统发育完整,大幅降低过敏病征诱发机率,但它在母乳中的含量会在哺乳至三个月后快速减少,一般乳制品不含有TGF-β2,主因为本身含量稀少,也无法保持其活性,只有特殊的萃取方式才能获得[2]
TGF-β2参与人体免疫反应TH1-TH2 的平衡
人体存在两种免疫反应,可分为
1. 第一型帮助型T细胞(TH1)媒介的正常免疫防御反应:
负责感染性微生物的免疫防御机转
若TH1细胞功能过度旺盛,引起发炎反应的细胞激素分泌,例如介白素-2(Interleukin-2, IL-2)和干扰素γ(Interferon-γ, IFN-γ)等,提升细胞性免疫反应,攻击人体的特定组织或特殊细胞,造成该人体某些组织或器官的长期的伤害,尤其是自体免疫疾病及器官移植排斥。
2. 第二型帮助型T细胞(TH2)媒介的过敏免疫防御反应:
负责寄生虫、叮咬虫类、过敏原与刺激物对障壁层器官的免疫防御机转
若TH2细胞功能过度旺盛,导致 TH2细胞激素分泌量过高,促使B细胞产生大量过敏抗体 IgE,IgE会诱发肥大细胞或嗜碱性白血球细胞释出发炎物质,如组织胺、介白素、细胞激素、血小板活化因子等,作用在细胞或血管上,造成血管舒张及平滑肌收缩,导致过敏性气喘、过敏性鼻炎、异位性皮肤炎等过敏症状产生。
此两种免疫力在人体内是以天秤式的平衡来呈现,TH1及TH2两者互相平衡,且共同受到调节型细胞 (Treg) 与免疫调节因子(TGF-β2)的调控,让身体免疫防御系统TH1及TH2维持平衡,即可达到预防自体免疫疾病及过敏相关疾病的作用。
结构
不同的TGF-β异构体间在结构上具有很高比例的相似(大约70~80%)。 整个TGF-β家族皆编码于一个巨大的蛋白前驱物上;TGF-β1具有390个胺基酸TGF-β2和TGF-β3具有412个胺基酸。
TGF-βN端皆具有一个长20~30个胺基酸序列作为讯号胜肽(TGF-β被分泌出细胞的讯号依据)也就是所谓的pro-region(latency associated peptide或称为LAP)。 后面112-114个C端胺基酸序列则在蛋白前驱物被裂解(proteolytic cleavage)后为成为成熟的TGF-β分子
成熟的TGF-β次单元会形成25 kDa有活性的二聚体(dimer),其中许多保守结构(conserved structural motifs) 。其中一个例子:整个TGF-β家族都有9个 半胱胺酸,这9个半胱胺酸中8个会2个为一组 双硫键形成cysteine knot,而这个结构即为整个TGF-β超家族的共同特征,第9个半胱胺酸则会与另外一个次单元的半胱胺酸形成双硫键产生双聚体。 其他的TGF-β保守结构多为借由疏水性交互作用(hydrophobic interactions)形成的二级结构。
第5跟第6个半胱胺酸之间含有最多胺基酸序列变异的区域,而这段区域即是TGF-β分子暴露在外,让不同受体对不同TGF-β辨认结合的区域。
功能
TGF-β可以结合到细胞表面的TGF-β受体结合而激活其受体。TGF-β受体是丝氨酸/苏氨酸激酶受体。[3]其信号传递可以通过SMAD信号通路[4] 和/或DAXX信号通路[5]
SMAD 途径
SMAD途径是TGF-β家族进行传递讯息的经典范例。 此途径会经过以下步骤进行讯息传递
- TGF-β双聚体会结合到 type II 受体
- type II受体会吸引并磷酸化type I受体
- 磷酸化后的type I受体吸引并磷酸化regulated SMAD(R-SMAD)
- 磷酸化后的R-SMAD会结合上common SMAD(coSMAD、SMAD4)并形成异元二聚体(heterodimeric complex)
- 该异元二聚体会进入细胞核中作为多种基因表现的转译因子,包括利用8种途径活化促分裂蛋白质激酶(mitogen-activated protein kinase)的产生,进而引发细胞凋亡。
而SMAD途径本身被回馈作用所调控,SMAD6与SMAD7可结合上type I受体,造成该受体无法与R-SMAD结合导致讯息中断
DAXX 途径
TGF-β也可能借由死亡相关蛋白(death associated protein 6 (DAXX adapter protein))启动细胞凋亡程序
现在已知DAXX会与type II的TGF-β受体激酶结合影响接下来对type I受体的磷酸化
细胞周期
TGF-β在调控细胞周期中扮演很重要的角色
TGF-β促使细胞合成p15与p21蛋白,而这两种蛋白会抑制可以把 Retinoblastoma protein (Rb) 蛋白磷酸化的 cyclin(细胞周期蛋白):CDK 复合体。也因此 TGF-β 可以间接抑制 c-myc 这个促进 G1期继续进行基因的表现[6]。
免疫系统
- TGF-β被认为能调控免疫系统中的Foxp3+调节T细胞:将effector T-cells(会攻击肿瘤细胞)转化成regulatory (suppressor) T-cells。以及能分化CD4+细胞中Foxp3+ Regulatory T cell 和 Th17 cells
- TGF-β的存在会停止活化淋巴球、单核球这类的吞噬细胞
细胞的发展与分化 TGF-β在某些情况下可以作为渐变式(graded)型态发生素,造成未成熟的细胞可以进行不同功能性的分化
临床意义
过敏相关疾病
TGF-β2改善过敏相关疾病:气喘、过敏性鼻炎、异位性皮肤炎、舒缓过敏症状,例如搔痒、气喘呼吸急促而费力胸闷等情形
- 降低52%呼吸道发炎细胞[7]
- 72%嗜酸性白血球浸润[7]
- 修复黏膜[7]
- 降低呼吸道阻力[7]
- 降低42% 过敏指数IgE[7]
- 降低Th2分泌的促发炎细胞素;减少84% IL-4、75% IL-5及51% IL-13[7]
- 诱导调节型T细胞(Treg) 增生、分化与活化,进而调控过敏免疫平衡[7]
- 降低产生黏液的mRNA,减少黏液分泌阻塞气管通道[8]
- 降低呼吸道IL-13刺激MUC5AC和MUC5B生成减少黏液分泌阻塞气管通道[8]
- 抵制iNOS产生,巩固对抗自由基的防御[9]
- 2013年国际权威期刊英国营养学期刊、2010&2011中华民国风湿暨免疫学会论文集中皆指出,TGF-β2对过敏、气喘与免疫失调相关疾病的病人提供相当机会降低类固醇的使用剂量。
- TGF-β2能预防及改善异位性皮肤炎:
➔ 异位性皮肤炎的妈咪,其宝宝亦受遗传因素影响,TGF-β含量相对较少[10]
➔ 人体研究发现:18位9.6个月的异位性皮肤炎的婴儿,体内TGF-β2明显不足,证实TGF-β2缺陷可能导致异位性皮肤炎[11]
➔ 9名异位性皮肤炎孩童(≤18岁)体内TGF-β2比正常人少29 %[12]
➔ 人体研究发现:TGF-β可预防异位性皮肤炎[13][14][15]
➔ 益生菌、鱼油改善异位性皮肤炎的作用,亦是透过TGF-β2[16][17]
➔ 哺喂母乳可降低宝宝异位性皮肤炎的风险,然而,过敏体质的母亲较正常母亲,其母乳中TGF-β2浓度约减少22%[18]
➔ TGF-β2可降低的异位性皮肤炎反复发作,可作为该类患者辅助治疗[19][20][21][22],有持续性异位性皮肤炎的幼儿,成长后较易发生呼吸道过敏疾病,因此,建
议在2岁以前减少异位性皮肤炎的严重度,有助于日后延缓过敏疾病
TGF-β2 可维持肠屏障稳健,改善食物过敏,降低肠道、气管、皮肤发炎,舒缓症状[23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]
- 维持肠道上皮黏膜功能完整性,防止过敏原渗漏进入肠粘膜
- 可保持肠屏障功能完整性,建立肠道免疫耐受性,降低Th2细胞所造成的过敏免疫发炎反应,故被认定有助于改善过敏
- 可促进IgA生产,增强肠上皮细胞屏障功能,在鼻、咽、气管、肠和膀胱粘膜的表面皆存在IgA,它能抑制毒素及微生物在黏膜上皮附著、减缓病毒繁殖、抵抗外来抗原进入体内。
- 新生儿肠道发育中,转化生长因子-β2(TGF-β2)扮演重要作用,新生儿肠道中TGF-β2生物活性来自于:肠上皮细胞和母乳,肠上皮细胞(IEC)是肠道中TGF-β2的主要来源的细胞
- TGF-β2可以保护新生儿肠黏膜发炎,新生儿内源性TGF-β2仍然不足,尤其在早产儿族群,TGF-β2在肠道的表现甚低,可能会影响生长发育,尤其易患坏死性小肠结肠炎(NEC),建议提早补充TGF-β2是提升人体免疫的新手段
- TGF-β2降低IEC细胞凋亡和NEC发展,从而使细胞体内平衡
- 口服摄入TGF-β2已确定可以促进新生儿-胃肠道的肠道屏障功能、提升免疫耐受性和粘膜修复
- 人体实验中发现,TGF-β2可抑制肠道巨噬细胞、细胞激素量和粘膜发炎反应
- 动物实验中发现,TGF-β2可以防止肠坏死,如新生儿坏死性结肠炎
- 早产的母亲,其母乳中TGF-β2含量少
- 在肠上皮细胞(IEC)中, TGF-β2主导抗发炎作用: 抑制促发炎细胞激素:IL-6及IL-8的分泌 、加强肠屏障功能,借由向上调节tight junction proteins 增加上皮细胞层修复 、TGF-β2 减少IFN- γ 和 IL-6、TGF-β2 抑制肠道中肥大细胞和嗜酸性粒细胞的浸润
- TGF-β2可调控肠粘膜细胞凋亡 ,机转为:调节细胞凋亡相关蛋白Bcl-xL和Bcl-2
- TGF-β2可保护胃肠道的适应症
- 饮食补充TGF-β2已被证明可缩小肠损伤并促进粘膜损伤后再生
- 口服TGF-β2可以预防粘膜损伤,增强p-ERK和b-catenin,进而增加的肠细胞增殖,减少肠细胞凋亡
- 过敏体质的母亲体内及母乳中TGF-β2浓度较低,TGF-β2浓度降低会干扰婴儿粘膜免疫系统的发展
- 天然存在的TGF-β2可以用于婴幼儿的功能性食物或作为特定肠道的治疗:活性TGF-β2饮食是有效的缓解Crohn’s disease patients、TGF-β2对细胞生长的影响最为人所知,在组织受伤或疾病期间, TGF-β2与血小板衍生因子共同刺激细胞增殖和细胞外基质产生,从而愈合或修复受伤的组织 、TGF-β2可以自分泌和旁分泌的方式起作用 、TGF-β2 控制淋巴细胞、巨噬细胞和树突状细胞的分化、增殖和活化状态,达到预防自身免疫和抗发炎
- 体外研究表示,TGF-β2抑制巨噬细胞和神经胶质瘤细胞MHC class II抗原,并调节MHC class I表现 :TGF-β2通过抑制MHC class II transactivator,进而抑制IFN- γ转录 、肠屏障是防止肠道毒素和细菌进入体内, TGF-β2可保持其完整性
- 人体临床实验证实 :七名儿童患有活动性小肠克罗恩病 (active small bowel Crohn’s disease) 给与富含TGF-β2的饮食8周,结果显示 :所有病患疾病皆获得改善,C反应蛋白质恢复正常,提高血清白蛋白和良好的体重增加 、回肠评估结果:六个孩童粘膜炎降低,且其中两个幼童完全康
- 新生儿粪便中分析TGF-β浓度,发现出生一年后,体内TGF-β降低5倍
- 母乳中TGF-β的存在,赋予婴幼儿在早期过敏保护作用,可协助IgA发挥作用并诱导Treg细胞活化。
- TGF-β减少游离抗原进入体内
TGF-β2降低 流感严重度及缩短病程
A型流感病毒H1N1是人类最常感染的流感病毒,感染后可能出现发烧、咳嗽、流鼻水、打喷嚏、肌肉酸痛、头痛或极度倦怠感等症状
TGF-β2降低流行性感冒病毒严重度及缩短病程[41]
- 肺部上皮细胞是流感病毒首要攻击目标
- 病毒使呼吸道反复发炎,造成正常免疫力下降,延长感冒病程
- TGF-β2是重要的抗发炎者
- 调节发炎分子
- 抑制TH1细胞产生发炎物质
- 保护肺部组织,避免遭受流感病毒诱发发炎
许多研究证实,鱼油及益生菌具有调整过敏体质的作用,研究也发现,两者好处的机转是透过TGF-β2达到增进免疫力,改善过敏体质
TGF-β2治疗干癣的临床实证
体外研究发现TGF-β2能抑制Th1相关细胞激素(IFN-γ及IL-2),显示TGF-β2可能改善Th1相关疾病,例如干癣。[44]
2005年一篇人体临床试验显示TGF-β2具改善牛皮癣严重度的潜力[45]
2007年更发表了一篇随机双盲研究,探讨TGF-β2改善干癣的效力及安全度,该研究收案42名轻至中度的干癣患者,随机双盲实验112天。效力评估主要从观察医师整体评估(physician's global assessment, PGA) 、干癣面积暨严重度指数(Psoriasis Area Severity Index ,PASI)、干癣体表面积(BSA)、痒的严重度来判别。研究结果显示,可明显改善干癣症状及生活品质。安全度性显示,高单位TGF-β2对肝、肾、血液指数无明显变化且不具有细胞毒性,不会增加感染率,证实其安全性。
2008年提出不同的剂量观点,一篇随机双盲性研究,TGF-β2连续服用56天,观察皮肤学生活品质量表(Dermatology Life Quality Index,DLQI)、医师整体评估(PGA)、痒的严重度,结果发现各指数均有明显的改变(p<0.05)。连续每天服用TGF-β2共56天,能改善轻-中度干癣患者的生活品质及降低疾病严度程度。机转为TGF-β2抑制IL-2及调整Treg细胞,而改善干癣的状况[46]
TGF-β2改善自体免疫相关疾病
研究指出TGF-β2亦能控制免疫细胞增生、分化与活化,当TGF-β2功能降低或丧失,会使免疫系统对自体组织的排斥,而导致自体免疫疾病,同时TGF-β2又具有诱导发炎细胞聚集的功能,故干癣、干燥症、红斑性狼疮、全身性硬化症、多发性硬化症、类风湿性关节炎等,皆和TGF-β2的功能异常有关[44]。[45][46][47][48][49][50]
TGF-β2改善干燥症
干燥症患者细胞因子失衡的特征:
在于促发炎细胞因子如IFN-γ,IL-12和IL-18的过度表达
重要的抗发炎细胞因子TGF-β太少,导致失去自身免疫的保护作用
维持眼部健康:
必须阻止‘促发炎的淋巴细胞(Th1和Th17类型)渗入眼中以引发促发炎细胞因子’
许多研究皆指出,Treg和TGFβ2具免疫调节功能
体内拥有足量抗发炎的淋巴细胞(Treg)和TGFβ-2,可避免免疫相关疾病(如干燥症)和发炎等紊乱的问题
补足体内抗发炎因子-TGF-β,有助于改善干燥症
TGF-β2改善肾脏纤维化[51]
肾小管和肾间质的纤维化,最终导致不可逆的肾功能衰退,进入末期肾病(ESRD)。
目前认为结缔组织生长因子(connective tissue growth factor,CTGF)是导致肾脏纤维化的主因,而TGF-β2可以活化sphingosine kinases-1 (SK-1),进而抑制CTGF表现,降低肾脏组织纤维化,延缓肾病变的进程
1. TGF-β2 大量表现在中枢神经系统,包括纹状体(striatum)、神经元和黑质(substantia nigra;SN) 的星状胶质细胞
2. 细胞及动物模式中,TGF-β2对神经细胞的生长,发育和分化具有直接影响力
3. 保护多巴胺神经元、提升存活率
4. 维持黑质纹状体多巴胺系统(Nigrostriatal pathway),稳定脑内多巴胺浓度
5. 协助GDNF的神经保护作用 ,阻止脑内神经细胞凋亡或进行修复
6. 防止毒性导致神经伤害
7. TGF- β 2基因变异时,容易导向巴金森氏症发生
8. 额外补充TGF- β 2可通过血脑障壁,快速抵达脑部作用[57]
癌症
越来越多证据显示,癌症归因于身体慢性发炎,体内长期慢性发炎,会刺激癌细胞生长,戒除引起发炎的根源,是减少癌症发生的好方法[58]
TGF-β2可降低体内发炎反应,并可快速修复黏膜组织,减少正常细胞病变风险。[59]
在正常的细胞,TGF-β会借由讯息传递将细胞周期停止在G1期以停止细胞的增殖、分化或是增进细胞凋亡的程序。补充TGF-β2可减少正常细胞病变,减少癌症的发生,但若体内已经有肿瘤存在,则需要更多临床研究验证相关机转。-[60]
心脏疾病
动物研究表明,胆固醇会抑制心血管细胞对TGF-β的回应进而造成TGF-β保护心血管细胞的能力下降,最后导致动脉粥状硬化以及其他心脏疾病的发生。 利用Statins(HMG-CoA还原抑制剂)这种药物会降低胆固醇浓度,其作用机制可能是借由提升心血管细胞对TGF-β的回应并恢复TGF-β对心血管细胞的保护能力[61]。
Marfan 症候群
TGF-β这类的讯号传递在Marfan症候群中扮演主要的发病因子[62],此种疾病的特征有以下几种:
- 具有不成比例的身高
- 患者常有蜘蛛趾(arachnodactyly),指节长度比平均值更高出许多
- 眼睛中的晶状体异位(ectopia lentis)
- 心脏方面的并发症如二尖瓣脱垂(mitral valve prolapse)、主动脉扩张(aortic enlargement)导致主动脉夹层(aortic dissection)产生的可能性
而这些并发症背后发病原理是因为患者无法合成第一型原纤维蛋白(fibrillin I),也就是弹性纤维(elastic fibers)的主成分。导致结缔组织的病变。在对小鼠的实验中,若对 Marfan患者施打TGF-β的拮抗剂会减缓上述症状的产生[63],其机制为减少原纤维蛋白(fibrillin)对 TGF-β的吸附能力。[64]
参看
外部链接
- Description of the TGF beta producing genes at ncbi.nlm.nih.gov
- Diagram of the TGF beta signaling pathway at genome.ad.jp
- The TGF-beta system — Nature Reviews Molecular Cell Biology
- SMART:TGFB domain annotation — European Molecular Biology Laboratory Heidelberg
- 医学主题词表(MeSH):TGF-beta
- Biochemists Solve Structure Of TGF-Beta And Its Receptor. 2008 Shows TGF-β3 dimer in TGFB-receptor.
- Measurement of Human Latent TGF-β1[永久失效链接]
- TGF beta pathway diagram
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