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100023 北京市2345信箱	世界华人消化杂志 2001年12月15日;9(12):1435-1438
Email: wcjd@public.bta.net.cn	世界华人消化杂志 ISSN 1009-3079 CN 14-1260/R
http:// www.wjgnet.com	版权归世界胃肠病学杂志社

⊙文献综述⊙

针刺对溃疡性结肠炎细胞因子的调控意义

田力黄裕新

中国人民解放军第四军医大学唐都医院消化科陕西省西安市 710038
国家自然科学基金资助,No.39970888
项目负责人 黄裕新.tianli72@263.net
电话 029-3577597
收稿日期 2001-11-02 接受日期 2001-11-29

摘要
溃疡性结肠炎(UC)是弥散的非特异性炎性肠病,免疫异常在其发病中占重要地位.有许多细胞因子参与了UC的炎症免疫反应,与其发病及转归密切相关.针刺具有良性调节神经- 内分泌-免疫作用,可以平衡调节UC中的致炎细胞因子和抗炎细胞因子,并取得良好的临床疗效.从细胞因子的整体调控水平来揭示 UC的发病机制及针刺治疗UC的可能作用机制，将为针刺治疗UC提供新的理论依据.

主题词 结肠炎,溃疡性/针灸疗法；结肠炎，溃疡性/病理生理学；细胞活素类/针灸效应；针刺

田力，黄裕新.针刺对溃疡性结肠炎细胞因子的调控意义. 世界华人消化杂志,2001;9(12):1435-1438

0 引言
溃疡性结肠炎（ulcerative colitis,UC）与克隆病（Crohn′s diseae, CD）同属于炎症性肠病（inflammatory bowel disease,IBD）,而UC是弥散的非特异性炎性肠病.其病因还不明确,考虑为感染,免疫,遗传和环境等综合因素所致,但免疫异常在其发病中占重要地位^［^1-4^］.有许多细胞因子参与了结肠粘膜的炎症免疫反应,与UC的发病及转归密切相关.针刺是我国传统医学的精华,近年研究表明针刺具有调节神经-内分泌-免疫的作用,并在临床上治疗UC取得了良好的疗效,相信随着研究的不断深入,细胞因子与UC之间的相互关系以及针刺对其调控作用和意义将会得到进一步的阐明. 细胞因子是由多种细胞所分泌的能调节细胞生长,分化及免疫功能,参与炎症发生和创伤愈合等小分子多肽的总称,包含白介素(interleu kin,IL),干扰素(interferon,IFN),肿瘤坏死因子(tumor necrosis factor,TNF),转化生长因子-β家族(transforming growth factor-β family,TGF-β)等.他们由淋巴细胞（特别是Th₁细胞和Th₂细胞）,单核细胞，肠巨核细胞，上皮细胞等产生.细胞因子在调节肠道炎症免疫反应中起关键作用.根据细胞因子在炎症反应中的作用不同分为两类：一类为致炎细胞因子（IL-1,IL-6,IL-8,TNF-α等）；另一类为抗炎细胞因子（IL-1ra,IL -4,IL-10,TGF-β等）.此外,根据T细胞因子的来源和免疫功能不同,将T细胞主要化分Th ₁和Th₂亚类.Th₁细胞主要分泌IL-2,TNF-α,IFN-γ等,称为Th₁样细胞因子,参与细胞免疫.Th₂细胞主要分泌IL-4,IL-10,IL-13等,称为Th₂样细胞因子,参与体液免疫及变态反应.致炎细胞因子与抗炎细胞因子之间或Th1样细胞因子与Th₂样细胞因子之间的平衡调节,对维持肠道正常免疫反应具有十分重要的病理生理意义.

1 细胞因子在UC发病和治疗中的意义
1.1 致炎细胞因子 致炎细胞因子可以对中性粒细胞等炎性细胞产生趋化作用,吸引其浸润肠道病变部位,发生一系列病变.IL-8还可以促进中性粒细胞溶酶体酶,超氧阴离子及白细胞三烯B4的释放,增加上皮细胞及单核细胞粘附分子的表达.致炎细胞因子也可刺激细胞毒T细胞及巨噬细胞的活性,促进他们的抗原呈递能力.他还使肠成纤维细胞产生过量的基质降解酶,破坏粘膜的完整性,形成溃疡^［⁵^］.TNF-α和IL-1等可引起结肠组织产生过多的NO,参与UC发生过程中的炎症反应和组织损伤.UC患者结肠粘膜IL-1β,IL-6,IL-8和TNF-α的mRNA表达明显增加.活动期UC患者结肠粘膜,直肠透析液及血清中 IL-1β，IL-6，IL-8和TNF-a水平明显升高,且这些细胞因子生成量与病情轻重及病变累及范围有关^［^6-9^］.提示UC患者免疫功能紊乱,致炎细胞因子使UC具有慢性炎症特征,其含量增高可能参与UC的发生和发展过程.
1.2 抗炎细胞因子 IL-4,IL-10和IL-13有下行调节免疫性,抑制IL-1β,IL-6,IL-8和TNF-α的分泌及其mRAN表达,并增加IL-1γα的生成,恢复IL-1rα/IL-1β的比率至正常水平^［^10,11^］.IL-4促进Th2细胞的增殖分化,IL-10抑制Th₁细胞增生,两者联合作用可以转换Th₁/Th₂细胞的激活,有助于Th₂免疫反应,这对抗炎和促进恢复是必要的^［¹²^］.UC时,过氧化物和溶酶体酶释放增多,诱导型NO合成酶（iNOS）活性增高,合成大量的NO,伴随产生过多的自由基,损伤组织,增强NK细胞的细胞毒性^［^13-17^］.IL-4和IL-13可延缓，抑制过氧化物产生,并抑制iNOS的表达和活性,调节NO的生成^［¹⁸^］. IL-10与IL-4或IL-13协同作用可有效抑制固有层单核细胞的溶酶体酶释放,并抑制单核/巨噬细胞的激活反应.IL-1rα可选择性地拮抗I L-1的致炎作用,并呈剂量效应.抗炎细胞因子生成紊乱或作用不足参与UC发病机制,有报道,UC 患者肠组织中IL-10 mRNA 表达减少,其炎性结肠粘膜固有层单核细胞产生IL-10减少及对rhIL-10反应减弱^［¹⁹^］. 但Autschbach et al^［²⁰^］用原位杂交和免疫组化方法发现UC患者炎性肠组织分泌IL-10的单核细胞数量明显增加,肠粘膜下IL-10表达增加,而固有层IL-10产生仍相对较低,提示肠粘膜局部单核细胞生成IL-10 不足,不能有效抑制固有层致炎细胞因子的生成.还有人实验证实UC患者血清IL-10浓度和肠粘膜IL-10 mRNA表达增加^［²¹^］.UC患者IL-10变化结果不一,可能与其他干扰因素有关.UC患者结肠组织IL-13浓度减低,活动期其浓度更低^［²²^］.但也有人提出UC患者活动期直肠粘膜IL-4和IL-13阳性表达增高^［²³^］.UC患者血管内皮生长因子(VEGF)水平明显增高,其活动期VEGF增高更显著,可能与IL-4免疫抑制效应缺乏有关^［²⁴^］.
1.3 致炎与抗炎细胞因子间失衡 UC患者IL-1ra/IL-1β比率下降可能参与UC的发病机制^［²⁵^］.Ishizuca et al^［²⁶^］用ELISA法证实在UC活动期患者结肠粘膜IL-1ra/IL-1β比率有下降趋势,在UC恢复期,该比率随IL-10和TGF浓度升高而升高.Bulois et al^［²⁷^］用RT-PCR方法分析患者的结肠粘膜发现:当UC患者组织学损伤评分>2分，中性粒细胞浸润>10%和有隐窝脓肿时,IL-10/IL-8 mRNA表达显著下降.IL-8和IL-10之间的失衡与结肠粘膜组织损伤有关.
1.4 细胞因子受体 可溶性IL-2受体(sIL-2R)作为一种封闭因子,与膜IL-2R竞争结合IL-2,降低IL-2水平,影响细胞免疫功能,还可部分地结合于B细胞膜上,产生异常的体液免疫反应,进而激活补体,导致组织炎症损伤.UC患者血清和肠粘膜内sIL-2R浓度升高,活动期其升高更明显 .累及全结肠的UC患者sIL-2R血清浓度高于只累及左结肠的UC患者,临床复发时伴随血清sIL-2R浓度升高,临床症状缓解和组织学改善时其浓度降低.可溶性IL-6受体(sIL-6R)与其他受体不同,sIL-6R与IL-6结合后可与细胞表面gp130结合,增强IL-6的活性.活动期UC患者,血清sIL-6R浓度明显升高，且其浓度与C 反应蛋白有显著相关性.可溶性TNF受体(sTNF-R)可与TNF特异结合,抑制TNF的活性.UC患者肠粘膜固有层单核细胞产生sTNF-R不增多,而TNF-α生成增多,造成sTNF-R和TNF-α之间失衡,从而不能有效抑制TNF的致炎作用.UC急性期患者尿sTNF-RP55和P75浓度明显增高，并与结肠炎活动指数（CAI）相关，可用来评价疾病活动及治疗效果.
1.5 其他 IL-7是胸腺T细胞增殖和分化的关键因子, 参与UC的免疫调节乱.IL-7mRNA在UC患者胸腺中表达增加，而在其结肠粘膜中表达降低.IL-7转基因鼠4～12周龄易患慢性结肠炎,其组织病理学与人的UC非常相似.IL-16可以增强致炎细胞因子的生成和表达,并促进CD4+和CD8+T淋巴细胞浸润炎性肠粘膜.UC患者炎性肠粘膜的IL-16mRNA及其蛋白质显著增高^［²⁸^］.白血病抑制因子(LIF)可促进IL-8合成, 具有趋化活性.UC患者LIF-1和IL-8同时显著增加.该患者肠病变区结缔组织生长因子(CTGF)，神经生长因子(NGF)和NGF高亲合力受体TrkA的mRNA表达及蛋白信号增强,有利于修复粘膜损伤,加速伤口愈合^［²⁹^］.IL-1ra基因多态性是否与UC易患性有关，一直有争论，但发现IL-1ra第2位等位基因及单型TNF-C与UC病情程度有显著关系^［^30,31^］.
1.6 细胞因子在UC治疗中的意义 鉴于细胞因子在UC发病机制中的作用,临床上已开始实验性运用新的UC治疗措施:包括给予重组抗炎细胞因子,实验发现IL-10联合使用IL-4或IL-13可增强疗效;给予致炎细胞因子拮抗剂或抗致炎细胞因子抗体,抑制致炎细胞因子的炎性作用;还可以给予细胞因子受体拮抗剂.这些治疗方案在临床实验阶段取得一定的疗效,但在正式用于临床之前还存在一些问题需要解决,如最佳给药途径，不良反应等^［^32-35^］.LK423和前列腺素E₂(PGE₂)因能调节细胞因子生成, 治疗UC大鼠模型有效^［^36,37^］.近年来尼古丁对结肠粘膜内炎症的调节作用受到人们的关注,尼古丁可降低UC患者或UC大鼠模型的结肠粘膜致炎细胞因子的水平^［^38-40^],但韩英et al^［⁴¹^］发现尼古丁因能促进IFN-γ和IL-12过量生成而加剧DSS诱导小鼠肠炎的肠粘膜损伤.尼古丁是否能引起UC组织学和临床症状的改善,尚需进一步证实.

2 神经内分泌免疫网络与UC
神经内分泌系统与免疫系统之间有密切的双向调节联系.免疫细胞上有多种神经内分泌激素受体,多种激素会影响免疫功能,免疫细胞也可以合成神经递质和激素影响内分泌系统.神经内分泌免疫系统紊乱与UC发病有关.胃肠肽类激素分泌和分布异常可直接参与UC发病机制^[⁴²^］,也可通过与细胞因子之间相互作用而参与UC发病.
2.1 胃肠激素对细胞因子的调节 生长激素抑制素(SOM)可抑制腹膜巨噬细胞和淋巴细胞生成IL-6和IFN-γ,也可与肠上皮细胞的特异受体结合, 抑制IL-8和IL-1β的自发产生或TNF-α诱导产生,这种抑制作用与IL-8和IL-1β的mRNA浓度有关^［^43-45^］.生长抑素(SS)可从蛋白质水平和mRNA水平抑制表皮生长因子诱导VEGF合成,并呈剂量依赖性^［⁴⁶^］.血管活性肠肽(VIP)可以增强激活的巨噬细胞分泌抗炎细胞因子^［⁴⁷^］.也有报道VIP可以减少脂多糖(LPS)刺激的巨噬细胞分泌TGF-β^［⁴⁸^］.VIP对腹膜巨噬细胞产生IL-6有双重作用,当LPS浓度为100ng·l^-1-10mg·l^-1时,VIP抑制IL-6的分泌;LPS浓度为1-10ng·l^-1时，VIP促进其分泌.神经肽(NPS)可直接结合于T细胞受体,使T细胞分泌IL-2,IFN-γ,IL-4和IL-10增加,还可促使Th₁和Th₂细胞分泌非典型的细胞因子，如Th₁细胞系分泌Th₂样细胞因子^［⁴⁹^］.胆囊收缩素8肽（CCK-8）可以抑制LPS对IL-1β,IL-6及TNF-α生成的诱导作用^［⁵⁰^］.
2.2 细胞因子对下丘脑-垂体的影响 IL-2刺激胆碱能神经纤维,激活神经NOS,使NO弥散地释放,增强促肾上腺皮质激素释放激素(GRH)的分泌,也可直接作用于垂体,促进促肾上腺皮质激素(ACTH)释放.IL-1β抑制NO诱导的黄体素释放激素(LHRH)的释放.IL-1α抑制生长激素释放激素(GHRH)和生长激素(GH)释放.IL-1可诱导卵泡刺激素(PRL)释放,并抑制PRL的抑制激素多巴胺的释放^［⁵¹^］.IL-2(-/-)鼠易患肠病，与人的UC极相似，该鼠结肠组织SP和VIP减少，结肠神经内分泌发生改变^［⁵²^］.细胞因子与神经内分泌激素相互作用相互调节,在正常人,这种调节是准确和精细的,使得致炎细胞因子和抗炎细胞因子之间处于平衡状态.UC病程中细胞因子和神经内分泌激素发生异常变化,上述平衡遭到破坏，可能是炎症发展的机制之一.

3 针刺与UC
3.1 针刺对神经-内分泌-免疫的影响针刺可影响神经内分泌激素和细胞因子的生成和表达,从而调节神经-内分泌-免疫网络^［^53-55^],实现双向的良性调节作用.电针刺大鼠足三里穴，发现脾IL-2和IFN-γ的水平升高及NK细胞的细胞毒性增强,并且IL-2和IFN-γ之间呈正相关,这些细胞因子的水平与NK细胞的活性有关,用IFN-γ中和抗体可完全阻断NK细胞活性及IFN-γ水平,提示内源性IFN-γ介导电针刺激NK细胞活性^［⁵⁶^］.手术创伤应激大鼠的脾淋巴细胞生成IL-2受抑制,针刺足三里穴及阑尾穴,可使IL-2生成增加,并可以改善损伤造成的免疫抑制效应.针刺还可以减轻脑缺血再灌注损伤,增强纹状体和大脑皮层成纤维细胞生长因子2(bFGF)的表达,使毛细血管开放数量增多,因此电针可通过调整血流动力学和增强内源性bFGF表达,保护神经组织^[⁵⁷^］.电针足三里穴可以使LPS刺激下过高的血清IL-1β,IL-6,TNF-α及NO水平降低^［⁶³^］,还可使血浆和胃液中表皮生长因子(EGF)水平上升^［⁵⁸^］.电针可增强针刺部位及外周血SP和VIP浓度,并诱导同经线上SP大量释放,使同经线上穴位内SP免疫阳性神经纤维数量明显减少^［^59,60^］.对于不同疾病电针可良性双向调节胃泌素的分泌.电针足三里穴可引起血浆SS含量降低,促胃液素(GT)含量升高^［^61,62^］.尽管国内外学者在针刺调节神经内分泌免疫系统的研究方面,作了大量细致有意义的工作,但尚缺少人们普遍接受的合理解释.
3.2 针刺对UC细胞因子的调控及治疗 现代腧穴学研究证明足三里,关元等穴具有增强机体免疫功能,与天枢，气海，太溪等穴相配能调整胃肠功能,改善肠道内环境而达到治疗目的.临床用针刺治疗UC取得了良好的疗效,且副作用小^［⁶⁴^］.有报道针刺UC模型大鼠,可使其结肠固有层异常增高的IL-1β和TNF-α阳性表达细胞显著减少^［⁶⁵^］.吴焕淦et al^［^66-68^］针刺UC模型大鼠的气海穴和天枢穴,用RT-PCR方法研究发现针刺可上调大鼠结肠粘膜和脾脏的抗炎细胞因子IL-1ramRNA表达,降低IL-1βmRNA，IL-6mRNA及iNOSmRNA表达,从而有效地控制UC已启动的炎症和免疫级联反应.上述研究结果为进一步从基因表达调控水平上研究UC提供了理论和实验基础.但在机体中,众多细胞因子及其基因是作为一个统一整体而发挥作用的.针刺是否会调控UC模型大鼠其他细胞因子,甚至深入到基因水平,至今尚未见报道.借鉴生命科学领域的先进理论与方法,从整体水平上研究针刺对UC细胞因子的调控,并深入至基因水平,将为最终揭示针刺治疗UC作用的本质提供了可能,同时也为针刺现代研究提供了很好的思路^［^69,70^］.只有充分地将针刺的特色融入到生命科学的领域中,将宏观现象与微观机制的研究紧密结合起来,针刺理论才能在当今迅速发展的生命科学领域得到丰富和发展. 总之,细胞因子生成，表达紊乱,和/或通过对胃肠神经内分泌的影响,造成胃肠神经-内分泌-免疫网络失衡,参与UC的发病和发展.针刺对胃肠-内分泌-免疫有良性调节作用,可以影响细胞因子和胃肠激素的生成及表达,从而达到治疗目的.但是,针刺治疗UC的机制尚不明确, 还需从细胞因子的整体调控水平来揭示UC的发病机制及针刺治疗UC的可能作用机制,为针刺治疗UC提供新的理论依据.

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