修回日期: 2010-06-28
接受日期: 2010-07-05
在线出版日期: 2010-08-08
Toll样受体(Toll-like receptors, TLRs)是近几年来发现的在宿主体内发挥重要免疫应答作用的细胞表面受体分子, 越来越多的证据表明TLRs可通过识别特定的模式分子, 激活特定的信号转导通路, 释放多种炎性介质和活性物质, 在消化系统脏器损伤中起着至关重要的作用, 如幽门螺杆菌(Helicobacter pylori, H. pylori)导致的胃黏膜损伤、酒精性胃炎、酒精性肝损伤、急性出血坏死性胰腺炎、肝缺血-再灌注损伤(ischemia/reperfusion injury, I/RI)、右旋硫酸钠(dextran sodium sulfate, DSS)诱导的结肠炎. 本文对TLRs与消化系统脏器损伤的关系进行综述, 初步探讨TLRs在消化系统疾病防治上的临床价值.
引文著录: 叶惠惠, 张咏梅. Toll样受体与消化系统损伤的研究进展. 世界华人消化杂志 2010; 18(22): 2339-2345
Revised: June 28, 2010
Accepted: July 5, 2010
Published online: August 8, 2010
Toll-like receptors (TLRs) are cell-surface molecules that play an important role in the host immune response. More and more evidence indicates that TLRs can recognize special pattern molecules to activate certain signal transduction pathways and result in the release of numerous inflammatory mediators and active substances to induce digestive system injury, such as Helicobacter pylori infection-induced gastric mucosal injury, alcohol-induced gastritis, alcohol-induced liver injury, acute hemorrhagic necrotizing pancreatitis, hepatic ischemia-reperfusion injury (I/RI), and dextran sodium sulfate (DSS)-induced colitis. Here, we review the advances in understanding the relationship between TLRs and digestive system injury and explore the clinical value of TLRs in the diagnosis and treatment of digestive system diseases.
- Citation: Ye HH, Zhang YM. Advances in understanding the relationship between Toll-like receptors and digestive system injury. Shijie Huaren Xiaohua Zazhi 2010; 18(22): 2339-2345
- URL: https://www.wjgnet.com/1009-3079/full/v18/i22/2339.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v18.i22.2339
Toll受体是在研究果蝇胚胎腹背侧体轴形成过程中发现的一种跨膜受体蛋白, 为模式识别受体, 在哺乳动物中Toll受体称为Toll样受体(Toll-like receptors, TLRs). 目前已发现TLRs家族共有13个成员, 其中对TLR2, TLR4的研究最多. 当机体受到病原微生物的侵袭时, TLR2主要识别革兰阳性菌的肽聚糖[1]、磷脂酸、脂蛋白等, 而TLR4主要识别革兰阴性菌的脂多糖(lipopolysaccharide, LPS)[1,2], 以上这些高度保守的分子结构常为一类或一群特定的病原微生物(及其产物)所共有, 称为病原相关分子模式(pathogen-associated molecular pattern molecules, PAMPs). 2002年, Matzinger[3]提出"危险模型(danger model)", 认为当机体收到危险信号时, 固有免疫反应更关注于来自周围组织的危险, 而非识别外来抗原, 为应对潜在危险, 细胞会释放内源性配体, 启动宿主免疫反应. 因此, 常将损伤或濒死细胞释放的正常细胞成分或组织损伤后蛋白酶反应并释放的细胞外基质成分称为损伤相关分子模式(damage-associated molecular pattern molecules, DAMPs)[4]. 越来越多的证据支持TLRs作为免疫系统中的重要膜受体, 可启动一系列与DAMPs有关的免疫反应[5-7]. Barsness等[8]也指出TLR4更倾向于是一种感受危险信号的受体, 而不是单纯的模式识别受体. 到目前为止发现他的内源性配体主要有高迁移率族蛋白1(high mobility group box 1 protein, HMGB1)[9]、热休克蛋白60(heat shock protein 60, HSP60)[10]、纤维蛋白原[11]、血管紧张素Ⅱ[12]、透明质酸[13]等, TLR2的内源性配体主要有HMGB1[9], HSP60[10]、淀粉体[14]、透明质酸[15]、抗磷脂抗体[16]等. 因此, 即使机体未受外源微生物的威胁, 亦可因为受到非病原微生物损伤而通过TLRs启动系统的炎症反应. TLRs的信号转导通路主要有: 依赖髓样分化因子(myeloid differentiation factor, MyD88)的途径和不依赖MyD88的途径. MyD88由含有死亡域的N端、中间区段、含有Toll/IL-1R同源结构域(TIR域)的C端组成, 是一种胞内转接蛋白分子, 当TLR4的TIR域活化后, MyD88可与TLR4作用, 激活下游的NF-κB, MAPK, IκB, IRF5信号通路, 从而表达炎性细胞因子[17]; TRIF(TIR domain-containing adaptor inducing IFN-β)是一重要的TIR域受体蛋白, 介导不依赖MyD88的信号通路, 一方面他通过C端的RHIM(Rip homotypic interaction motif)与RIP1(receptor-interacting protein 1)结合, 进一步激活NF-κB和MAPK信号通路; 另一方面, 他还可通过TRAF3(TNF receptor-associated factor 3)激活IRF3信号通路, 从而诱导Ⅰ型干扰素等的转录[17]. 研究发现: TLR4, TLR2可在健康大鼠的消化系黏膜上结构性表达, 其中TLR4主要在胃和远端结肠上表达, TLR2主要在近端结肠上表达, 而MyD88在整个消化系统表达一致[18]. 正常情况下, 消化系统的保护机制和损伤机制处于一种动态平衡状态, 不会引起机体病理反应. 一旦打破这种平衡, 消化系统各脏器就可能出现病理性损伤, 表现出临床症状, 有时可进一步发展成癌症. 其中, 免疫系统为保护脏器抵御不同的损伤, 可释放多种细胞因子和化学因子, 而TLRs又能通过信号转导通路释放大量的炎性因子, 因此消化系统损伤必定与TLRs存在关联. 我们就近年来有关TLRs及消化系统损伤的相关研究, 作如下综述.
H. pylori感染可导致胃黏膜受损, 他与胃、十二指肠溃疡病、胃底部腺癌、胃淋巴细胞增生性疾病如淋巴瘤等疾病密切相关. H. pylori可引起机体发生特异性的体液免疫及细胞免疫, 这与他的毒力因子有关. 细胞空泡毒素(vacuolating cytotoxin, VacA)是H. pylori十分重要的致病因子, 是细菌毒性的重要标志之一, 他通过干扰细胞内离子转运蛋白即空泡型ATP酶的功能而起作用, 此外, 还可作用于Na+-K+-ATP酶, 抑制该酶的活性造成细胞水肿. 细胞毒素相关蛋白(cytotoxin-associated protein A, CagA)常与VacA同时出现, 他具有高度的免疫原性, 能引起强烈的免疫反应, 且与毒性增加有关. H. pylori还能产生一种在发病机制中起作用的尿素酶, 他能将尿素分解为CO2和NH3, NH3可以中和胃内的盐酸, 可使H. pylori置身于强酸环境中而不致遭到破坏, 从而使H. pylori能在胃内定居. HSP可以激活细胞免疫反应, 刺激γδT细胞, 从而损伤胃组织, 产生交叉免疫反应, 引起炎性损伤, 参与尿素酶的合成和转运及分子的稳定. H. pylori的黏附素、LPS、分泌的趋化因子以及其他类似于氧化酶、过氧化氢酶等的因子均可引起H. pylori感染所致的临床症状.
人类胃上皮细胞AGS可结构性表达TLR4[19], 而H. pylori感染可诱导TLR4的基因转录[20]. 蛋白免疫印迹结果显示当H. pylori与胃癌MKN 45胃黏膜上皮细胞一起孵育6 h后, Ⅰ型H. pylori可增加糖基化TLR4水平, 而Ⅱ型H. pylori却没有这种作用, 这说明CagA可上调TLR4的表达进而促进胃癌的发生[19]. H. pylori致病的一个先决条件是在胃内长期定植. 为了研究TLRs可否作为H. pylori的一种黏合机制, 研究者们采用扫描电子显微镜、流式细胞仪细菌测定技术发现, 与转染了TLR2及未转染TLR4的CHO细胞株相比, 转染TLR4的CHO细胞株的黏附作用显著增强, 可见H. pylori可利用TLR4作为一种受体以黏附到宿主细胞表面[19]. Uno等[21]在正常小鼠胃黏膜细胞GSM 06上观察到: TLR2可协同TLR4增加H. pylori感染后iNOS和NO的表达, H. pylori LPS可上调TLR2的表达并激活其下游NF-κB信号转导通路, 而给予TLR4 siRNA干扰后, TLR2表达下降, NF-κB信号转导通路的活化被抑制, 提示在GSM 06细胞上, TLR2的诱导可能来自TLR4与H. pylori LPS的交互作用. 同时, TLRs基因的多态性与H. pylori感染导致的临床疾病亦有关联. 研究发现, TLR4 Asp299Gly和Thr399ILeu的基因多态性是H. pylori感染者胃癌和癌前病变的易感因素[22], 而TLR4+3725G/C的基因多态性是日本H. pylori感染者易发生萎缩性胃炎的高危因素[23].
在胃黏膜受损前后, TLRs的分布亦可出现变化. 有研究人员报道在无H. pylori感染时, TLR4主要在胃体表达, 而感染后则在胃窦、胃体高度表达[24]. 通过荧光共聚焦显微镜发现TLR4在H. pylori感染前后均分布于胃上皮的顶端和基底外侧, 而TLR5, TLR9在感染前分布与TLR4相似, 但在感染后只出现于基底外侧, 可见TLR5, TLR9的亚细胞分布并非是静止的, 而是一个似乎由H.pylori感染所调节的动态过程[25]. 这提示了TLRs在宿主对H. pylori感染的固有免疫中可能发挥着"哨兵"的作用.
酒精对胃黏膜的损伤包括急性及慢性两方面, 前者主要表现为急性糜烂性胃炎甚至溃疡, 与非甾体类抗炎药协同作用对胃黏膜的损伤更为显著, 后者主要表现为胃肠黏膜糜烂伴有上皮代偿性增生, 时间较长可出现肠上皮化生、上皮不典型增生, 甚至癌变. 急性酗酒所致的急性糜烂性胃炎是临床上常见的上消化系出血原因之一, 了解酒精对胃黏膜的损伤具有重要意义. Zhang等[26]利用普通近交系小鼠C57BL/6J、TLR4野生型小鼠C3H/HeOuJ、TLR4突变型小鼠C3H/HeJ进行酒精灌胃以建立酒精导致的胃黏膜损伤模型, 4 h后将小鼠处死发现TLR4信号被激活, C3H/HeJ小鼠胃黏膜损伤程度重于C3H/HeOuJ小鼠, 同时环氧酶-2(cyclooxygenase-2, COX-2)、前列腺素E2(prostaglandin E2, PGE2)、巨噬细胞、巨噬细胞炎性蛋白-2(macrophage-inflammatory protein-2, MIP-2)的表达仅在C3H/HeOuJ小鼠胃黏膜上增加, 并由此推断出TLR4通过诱导表达COX-2和产生PGE2对酒精诱导的胃黏膜损伤起保护作用.
饮酒后乙醇有90%-95%在肝内代谢, 因此可对肝产生很大的损伤, 且损伤程度与乙醇剂量、接触时间呈正相关[27]. 乙醇可导致胞质内毒素水平增高[27], 而内毒素通过与CD14的相互作用引起肝损伤, 但是CD14并不含有跨膜序列, 不能直接诱导细胞内信号转导通路导致细胞产生毒性反应, 因此必定存在一个跨膜受体蛋白能介导这一过程, 研究人员发现TLR4即可参与这个过程[27-30], 且这一过程并不依赖于MyD88[29]. 通过激光扫描共焦显微镜观察到在给予酒精的实验组中, TLR4阳性细胞数明显多于对照组, 且8 wk的免疫荧光强度>4 wk, RT-PCR结果也显示TLR4 mRNA水平高于对照组[28]. Gustot等[30]发现给予小鼠TLR4的配体LPS后, 酒精性肝损伤模型小鼠肝脏上TNF-α mRNA的表达显著强于对照组小鼠肝脏上TNF-α mRNA的表达, 提示酒精可增加肝脏对细菌产物所致炎症的敏感性. 由细胞色素P450和烟酰胺腺嘌呤二核苷酸磷酸(nicotinamide adenine dinucleotide phosphate, NADP)复合物所释放的氧自由基促进酒精对肝的损伤, 但是研究发现在TLR4基因缺陷型小鼠体上, 细胞色素P450和NADP复合物的表达和激活显著减少, 但在MyD88缺陷型小鼠体上却未有这种情况出现[29]. 在TLR4基因缺陷型小鼠体上, 酒精导致的肝损害可显著减弱, TNF-α表达也未见增加[28]. 以上研究结果说明TLR4可促进酒精性肝病的发生, 但并没有通过MyD88信号通路发挥作用.
急性出血坏死性胰腺炎常继发感染、腹膜炎、休克等多种并发症, 病情险恶, 死亡率高. 引起胰腺炎的病因常有胆道疾病、过量饮酒、十二指肠液反流、创伤因素、胰腺血循环障碍、药物因素等. 此病常可导致多器官功能障碍综合征, 对肝脏的损害常表现为肝功能障碍, 甚至导致肝功能衰竭[31]. Zhang等[31]利用大鼠进行实验, 发现急性出血坏死性胰腺炎可导致肝内谷丙转氨酶、谷草转氨酶浓度显著增高, 可见肝功能严重受损. 在抑制TLR2/4 mRNA表达后, NO浓度增加, TNF-α浓度降低, 同时肝组织损伤程度明显降低. 可见TLR2/4 mRNA的表达在急性出血坏死性胰腺炎导致肝损伤的发病、发展中起重要作用.
由于肝脏的血液供应丰富, 对缺血敏感, 耐受缺血能力差, 肝移植术后不可避免会产生缺血-再灌注损伤(ischemia/reperfusion injury, I/RI). 肝脏I/RI后由于活性氧生成增多、诱导型一氧化碳合酶增加、炎性细胞因子释放、细胞黏附分子表达增加, 引起Kupffer细胞激活、肝窦上皮细胞凋亡及中性粒细胞汇聚[32]. Kupffer细胞可表达TLR4、MD-2 mRNA和蛋白, 肝移植后由于肝脏发生I/RI, 他们的表达显著增加[33]. 用敲除TLR4基因(TLR4-/-)的小鼠制备模型, 结果发现来自TLR4-/-供体小鼠的肝脏不管是被移植入野生型小鼠还是TLR4-/-小鼠, I/RI都得到了极大改善, 且伴随以下指标的变化: (1)肝内IFN-γ诱导蛋白10(interferon-gamma-inducible protein 10, CXCL 10)、细胞间黏附分子-1(intercellular adhesion molecule, ICAM-1)表达降低、局部中性粒细胞和CD4+ T细胞浸润减弱; (2)TNF-α, IFN-γ, IL-1β, IL-2等Th1细胞因子减少, 而IL-4, IL-10等Th2细胞因子表达显著增加; (3)肝内细胞凋亡减少, caspase-3活性降低, 抗氧化剂HO-1上调[34]. TLR4不仅能通过内毒素LPS参与肝脏I/RI, Zhai等[35]发现TLR4还能通过他的内源性配体热敏感蛋白分子使巨噬细胞活性增高, 释放TNF-α. 以上研究均说明TLR4参与肝脏I/RI[33-38], 且TLR4-/-还与许多介导I/RI的通路有关: (1)抑制凋亡细胞活性、增加抗氧化蛋白表达、降低活性氧浓度[34]; (2)抑制线粒体后凋亡、影响凋亡复合体的形成[39]; (3)可能通过p38有丝分裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)[40]或信号转导因子和转录激活因子6(signal transducer and activator of transcription 6, STAT6)[41]增强抗炎/抗凋亡通路; (4)可能通过减弱NF-κB[42]或IRF3[43]信号通路抑制各种炎性细胞因子的释放.
坏死性小肠结肠炎是新生儿死于消化系疾病的重要原因[44], 以肠出血、坏死、穿孔为主要临床特征, 临床进展急骤, 可迅速发展成全身性败血症、多器官功能衰竭, 甚至死亡, 在美国病死率高达15%[45]. 当发生坏死性小肠结肠炎时, 肠黏膜TLR4表达可增加, 进一步给予低氧刺激后, TLR4 mRNA和蛋白表达增加, 坏死性小肠结肠炎病情恶化[46]. 此外研究发现给予小鼠窒息处理后, TLR4野生小鼠肠腔中细菌的毒性作用明显增强[47], 坏死性小肠结肠炎病情的恶化程度在TLR4野生小鼠显著强于TLR4突变小鼠[47,48]. 细胞黏附蛋白FAK在调节细胞凋亡、迁移、增殖方面起着重要作用[48], 他与MyD88之间存在交互作用[49], Leaphart等[46]发现在坏死性小肠结肠炎的恶化过程中, TLR4可促进FAK的磷酸化, 导致细胞凋亡增加, 细胞增殖和迁移能力降低, 从而诱导细胞损伤, 破坏肠道的修复机制. 以上研究结果说明TLR4可促进坏死性小肠结肠炎病情的恶化.
肠道内细菌多种多样, 不仅存在致病菌, 还有许多在正常情况下维持肠道功能的共生微生物, 因此肠道免疫系统常面临着双重压力, 既要保护宿主抵抗致病菌感染, 还要维持机体对共生微生物的正常反应. DSS可诱导小肠上皮细胞凋亡, 抑制细胞分化, 引起上皮损伤、急慢性炎细胞渗透, 导致结肠炎[50,51]. 在DSS诱导的急性结肠炎小鼠模型上, TLR4-/-, MyD88-/-小鼠的急性炎细胞浸润情况比对照组小鼠轻, 但是肠道出血出现早且情况更严重, 肠系膜淋巴结也易聚积革兰阴性菌[50]. 由单核细胞、巨噬细胞表达的MIP-2能发挥趋化作用[52,53], 使中性粒细胞聚集至小肠黏膜. 在TLR4-/-, MyD88-/-小鼠黏膜固有层上可见MIP-2表达减少, 中性粒细胞聚集程度减弱, 说明TLRs信号可对MIP-2进行调节[50,52]. 以上实验结果提示了TLR4通过MyD88信号通路对急性肠损伤起着重要作用. 脊椎蛋白2(Mindin)作为细胞外基质蛋白, 是一种模式识别受体, 可通过整合素和致病微生物启动固有免疫反应[54]. Guleng等[55]发现在DSS诱导的结肠炎中, Mindin mRNA表达增加, NF-κB信号转导通路激活, 而其中起介导作用的为TLR9, 这提示了TLRs不仅自身可发挥固有免疫反应作用, 还能间接地帮助其他具有固有免疫反应功能的物质协同促进结肠炎的发生发展.
TLRs及其信号转导通路在胃黏膜损伤、肝脏损伤、肠道损伤等消化系损伤中发挥重要的作用. 但目前对此方面的研究多着重于TLR4, TLR2. 随着对TLRs进一步的认识, 其他TLRs也将成为这一研究的热点. 并且, 通过影响TLRs信号通路对消化系损伤进行治疗也将成为现实.
当消化系统受到病理性损伤时, 机体免疫系统可产生一系列反应以保护机体免受进一步损伤, 而TLRs作为免疫系统中重要的膜受体, 可通过识别特定的模式分子和激活特定的信号转导通路, 发挥其固有免疫应答的作用.
冯志杰, 主任医师, 河北医科大学第二医院消化内科
在消化系统损伤中, TLRs可识别损伤相关分子模式以发挥固有免疫应答作用, 但目前研究多着重于TLR4、TLR2, 对其他成员的研究相对较少, 且所报道的损伤相关分子模式的种类也较局限.
TLRs通过识别病原相关分子模式对消化系疾病产生免疫调节作用, 并经科学研究证实TLRs及其信号转导通路在胃黏膜损伤、肝脏损伤、肠道损伤等消化系统损伤中发挥重要作用.
本文综合众多学者的研究结果, 更全面地阐述在消化系损伤中, TLRs可识别损伤相关分子模式以发挥固有免疫应答作用, 以进一步说明TLRs在消化系统疾病中的多方面作用.
本文提示TLRs可为治疗消化系统损伤提供新的药物靶点, 扩展了临床上消化系统疾病的治疗途径.
本文内容全面, 参考文献引用合理, 具有一定的理论价值.
编辑:曹丽鸥 电编:何基才
| 1. | Massonnet B, Delwail A, Ayrault JM, Chagneau-Derrode C, Lecron JC, Silvain C. Increased immunoglobulin A in alcoholic liver cirrhosis: exploring the response of B cells to Toll-like receptor 9 activation. Clin Exp Immunol. 2009;158:115-124. [PubMed] [DOI] |
| 2. | Eckert M, Wittmann I, Röllinghoff M, Gessner A, Schnare M. Endotoxin-induced expression of murine bactericidal permeability/increasing protein is mediated exclusively by toll/IL-1 receptor domain-containing adaptor inducing IFN-beta- dependent pathways. J Immunol. 2006;176:522-528. [PubMed] |
| 3. | Matzinger P. The danger model: a renewed sense of self. Science. 2002;296:301-305. [PubMed] [DOI] |
| 4. | Tsung A, Klune JR, Zhang X, Jeyabalan G, Cao Z, Peng X, Stolz DB, Geller DA, Rosengart MR, Billiar TR. HMGB1 release induced by liver ischemia involves Toll-like receptor 4 dependent reactive oxygen species production and calcium-mediated signaling. J Exp Med. 2007;204:2913-2923. [PubMed] [DOI] |
| 5. | Wakefield D, Gray P, Chang J, Di Girolamo N, McCluskey P. The role of PAMPs and DAMPs in the pathogenesis of acute and recurrent anterior uveitis. Br J Ophthalmol. 2010;94:271-274. [PubMed] [DOI] |
| 6. | Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007;81:1-5. [PubMed] [DOI] |
| 7. | Erridge C. Endogenous ligands of TLR2 and TLR4: agonists or assistants? J Leukoc Biol. 2010;87:989-999. [PubMed] [DOI] |
| 8. | Barsness KA, Arcaroli J, Harken AH, Abraham E, Banerjee A, Reznikov L, McIntyre RC. Hemorrhage-induced acute lung injury is TLR-4 dependent. Am J Physiol Regul Integr Comp Physiol. 2004;287:R592-R599. [PubMed] [DOI] |
| 9. | Devaraj S, Dasu MR, Park SH, Jialal I. Increased levels of ligands of Toll-like receptors 2 and 4 in type 1 diabetes. Diabetologia. 2009;52:1665-1668. [PubMed] [DOI] |
| 10. | de Graaf R, Kloppenburg G, Kitslaar PJ, Bruggeman CA, Stassen F. Human heat shock protein 60 stimulates vascular smooth muscle cell proliferation through Toll-like receptors 2 and 4. Microbes Infect. 2006;8:1859-1865. [PubMed] [DOI] |
| 11. | Hodgkinson CP, Patel K, Ye S. Functional Toll-like receptor 4 mutations modulate the response to fibrinogen. Thromb Haemost. 2008;100:301-307. [PubMed] |
| 12. | Ji Y, Liu J, Wang Z, Liu N. Angiotensin II induces inflammatory response partly via toll-like receptor 4-dependent signaling pathway in vascular smooth muscle cells. Cell Physiol Biochem. 2009;23:265-276. [PubMed] [DOI] |
| 13. | Gariboldi S, Palazzo M, Zanobbio L, Selleri S, Sommariva M, Sfondrini L, Cavicchini S, Balsari A, Rumio C. Low molecular weight hyaluronic acid increases the self-defense of skin epithelium by induction of beta-defensin 2 via TLR2 and TLR4. J Immunol. 2008;181:2103-2110. [PubMed] |
| 14. | Tükel C, Wilson RP, Nishimori JH, Pezeshki M, Chromy BA, Bäumler AJ. Responses to amyloids of microbial and host origin are mediated through toll-like receptor 2. Cell Host Microbe. 2009;6:45-53. [PubMed] [DOI] |
| 15. | Scheibner KA, Lutz MA, Boodoo S, Fenton MJ, Powell JD, Horton MR. Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. J Immunol. 2006;177:1272-1281. [PubMed] |
| 16. | Satta N, Dunoyer-Geindre S, Reber G, Fish RJ, Boehlen F, Kruithof EK, de Moerloose P. The role of TLR2 in the inflammatory activation of mouse fibroblasts by human antiphospholipid antibodies. Blood. 2007;109:1507-1514. [PubMed] [DOI] |
| 17. | Lu YC, Yeh WC, Ohashi PS. LPS/TLR4 signal transduction pathway. Cytokine. 2008;42:145-151. [PubMed] [DOI] |
| 18. | Ortega-Cava CF, Ishihara S, Rumi MA, Kawashima K, Ishimura N, Kazumori H, Udagawa J, Kadowaki Y, Kinoshita Y. Strategic compartmentalization of Toll-like receptor 4 in the mouse gut. J Immunol. 2003;170:3977-3985. [PubMed] |
| 19. | Su B, Ceponis PJ, Lebel S, Huynh H, Sherman PM. Helicobacter pylori activates Toll-like receptor 4 expression in gastrointestinal epithelial cells. Infect Immun. 2003;71:3496-3502. [PubMed] [DOI] |
| 20. | Zhou C, Ma FZ, Deng XJ, Yuan H, Ma HS. Lactobacilli inhibit interleukin-8 production induced by Helicobacter pylori lipopolysaccharide-activated Toll-like receptor 4. World J Gastroenterol. 2008;14:5090-5095. [PubMed] [DOI] |
| 21. | Uno K, Kato K, Atsumi T, Suzuki T, Yoshitake J, Morita H, Ohara S, Kotake Y, Shimosegawa T, Yoshimura T. Toll-like receptor (TLR) 2 induced through TLR4 signaling initiated by Helicobacter pylori cooperatively amplifies iNOS induction in gastric epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2007;293:G1004-G1012. [PubMed] [DOI] |
| 22. | Achyut BR, Ghoshal UC, Moorchung N, Mittal B. Association of Toll-like receptor-4 (Asp299Gly and Thr399Ileu) gene polymorphisms with gastritis and precancerous lesions. Hum Immunol. 2007;68:901-907. [PubMed] [DOI] |
| 23. | Hishida A, Matsuo K, Goto Y, Mitsuda Y, Hiraki A, Naito M, Wakai K, Tajima K, Hamajima N. Toll-like receptor 4 +3725 G/C polymorphism, Helicobacter pylori seropositivity, and the risk of gastric atrophy and gastric cancer in Japanese. Helicobacter. 2009;14:47-53. [PubMed] [DOI] |
| 24. | Asahi K, Fu HY, Hayashi Y, Eguchi H, Murata H, Tsujii M, Tsuji S, Tanimura H, Kawano S. Helicobacter pylori infection affects Toll-like receptor 4 expression in human gastric mucosa. Hepatogastroenterology. 2007;54:1941-1944. [PubMed] |
| 25. | Schmausser B, Andrulis M, Endrich S, Lee SK, Josenhans C, Müller-Hermelink HK, Eck M. Expression and subcellular distribution of toll-like receptors TLR4, TLR5 and TLR9 on the gastric epithelium in Helicobacter pylori infection. Clin Exp Immunol. 2004;136:521-526. [PubMed] [DOI] |
| 26. | Zhang Y, Chen H, Yang L. Toll-like receptor 4 participates in gastric mucosal protection through Cox-2 and PGE(2). Dig Liver Dis. 2010;42:472-476. [PubMed] [DOI] |
| 27. | Zuo G, Gong J, Liu C, Wu C, Li S, Dai L. Synthesis of Toll-like receptor 4 in Kupffer cells and its role in alcohol-induced liver disease. Chin Med J (Engl). 2003;116:297-300. [PubMed] |
| 28. | Uesugi T, Froh M, Arteel GE, Bradford BU, Thurman RG. Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice. Hepatology. 2001;34:101-108. [PubMed] [DOI] |
| 29. | Hritz I, Mandrekar P, Velayudham A, Catalano D, Dolganiuc A, Kodys K, Kurt-Jones E, Szabo G. The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88. Hepatology. 2008;48:1224-1231. [PubMed] [DOI] |
| 30. | Gustot T, Lemmers A, Moreno C, Nagy N, Quertinmont E, Nicaise C, Franchimont D, Louis H, Devière J, Le Moine O. Differential liver sensitization to toll-like receptor pathways in mice with alcoholic fatty liver. Hepatology. 2006;43:989-1000. [PubMed] [DOI] |
| 31. | Zhang L, Wu HS, Chen Y, Guo XJ, Wang L, Wang CY, Zhang JH, Tian Y. Role of nitric oxide in Toll-like receptor 2 and 4 mRNA expression in liver of acute hemorrhagic necrotizing pancreatitis rats. World J Gastroenterol. 2006;12:485-488. [PubMed] |
| 32. | Fondevila C, Busuttil RW, Kupiec-Weglinski JW. Hepatic ischemia/reperfusion injury--a fresh look. Exp Mol Pathol. 2003;74:86-93. [PubMed] [DOI] |
| 33. | Peng Y, Gong JP, Liu CA, Li XH, Gan L, Li SB. Expression of toll-like receptor 4 and MD-2 gene and protein in Kupffer cells after ischemia-reperfusion in rat liver graft. World J Gastroenterol. 2004;10:2890-2893. [PubMed] |
| 34. | Shen XD, Ke B, Zhai Y, Gao F, Tsuchihashi S, Lassman CR, Busuttil RW, Kupiec-Weglinski JW. Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model. Liver Transpl. 2007;13:1435-1443. [PubMed] [DOI] |
| 35. | Zhai Y, Qiao B, Shen XD, Gao F, Busuttil RW, Cheng G, Platt JL, Volk HD, Kupiec-Weglinski JW. Evidence for the pivotal role of endogenous toll-like receptor 4 ligands in liver ischemia and reperfusion injury. Transplantation. 2008;85:1016-1022. [PubMed] [DOI] |
| 36. | Shen XD, Ke B, Zhai Y, Gao F, Busuttil RW, Cheng G, Kupiec-Weglinski JW. Toll-like receptor and heme oxygenase-1 signaling in hepatic ischemia/reperfusion injury. Am J Transplant. 2005;5:1793-1800. [PubMed] [DOI] |
| 37. | Jin X, Wang L, Wu HS, Zhang L, Wang CY, Tian Y, Zhang JH. N-acetylcysteine inhibits activation of toll-like receptor 2 and 4 gene expression in the liver and lung after partial hepatic ischemia-reperfusion injury in mice. Hepatobiliary Pancreat Dis Int. 2007;6:284-289. [PubMed] |
| 38. | Ellett JD, Evans ZP, Atkinson C, Schmidt MG, Schnellmann RG, Chavin KD. Toll-like receptor 4 is a key mediator of murine steatotic liver warm ischemia/reperfusion injury. Liver Transpl. 2009;15:1101-1109. [PubMed] [DOI] |
| 39. | Antoku K, Maser RS, Scully WJ Jr, Delach SM, Johnson DE. Isolation of Bcl-2 binding proteins that exhibit homology with BAG-1 and suppressor of death domains protein. Biochem Biophys Res Commun. 2001;286:1003-1010. [PubMed] [DOI] |
| 40. | Amersi F, Shen XD, Anselmo D, Melinek J, Iyer S, Southard DJ, Katori M, Volk HD, Busuttil RW, Buelow R. Ex vivo exposure to carbon monoxide prevents hepatic ischemia/reperfusion injury through p38 MAP kinase pathway. Hepatology. 2002;35:815-823. [PubMed] [DOI] |
| 41. | Shen XD, Ke B, Zhai Y, Gao F, Anselmo D, Lassman CR, Busuttil RW, Kupiec-Weglinski JW. Stat4 and Stat6 signaling in hepatic ischemia/reperfusion injury in mice: HO-1 dependence of Stat4 disruption-mediated cytoprotection. Hepatology. 2003;37:296-303. [PubMed] [DOI] |
| 42. | Wang H, Li ZY, Wu HS, Wang Y, Jiang CF, Zheng QC, Zhang JX. Endogenous danger signals trigger hepatic ischemia/reperfusion injury through toll-like receptor 4/nuclear factor-kappa B pathway. Chin Med J (Engl). 2007;120:509-514. [PubMed] |
| 43. | Zhai Y, Shen XD, O'Connell R, Gao F, Lassman C, Busuttil RW, Cheng G, Kupiec-Weglinski JW. Cutting edge: TLR4 activation mediates liver ischemia/reperfusion inflammatory response via IFN regulatory factor 3-dependent MyD88- independent pathway. J Immunol. 2004;173:7115-7119. [PubMed] |
| 44. | Anand RJ, Leaphart CL, Mollen KP, Hackam DJ. The role of the intestinal barrier in the pathogenesis of necrotizing enterocolitis. Shock. 2007;27:124-133. [PubMed] [DOI] |
| 45. | Miniño AM, Heron MP, Murphy SL, Kochanek KD. Deaths: final data for 2004. Natl Vital Stat Rep. 2007;55:1-119. [PubMed] |
| 46. | Leaphart CL, Cavallo J, Gribar SC, Cetin S, Li J, Branca MF, Dubowski TD, Sodhi CP, Hackam DJ. A critical role for TLR4 in the pathogenesis of necrotizing enterocolitis by modulating intestinal injury and repair. J Immunol. 2007;179:4808-4820. [PubMed] |
| 47. | Jilling T, Simon D, Lu J, Meng FJ, Li D, Schy R, Thomson RB, Soliman A, Arditi M, Caplan MS. The roles of bacteria and TLR4 in rat and murine models of necrotizing enterocolitis. J Immunol. 2006;177:3273-3282. [PubMed] |
| 48. | Basson MD, Sanders MA, Gomez R, Hatfield J, Vanderheide R, Thamilselvan V, Zhang J, Walsh MF. Focal adhesion kinase protein levels in gut epithelial motility. Am J Physiol Gastrointest Liver Physiol. 2006;291:G491-G499. [PubMed] [DOI] |
| 49. | Semaan N, Alsaleh G, Gottenberg JE, Wachsmann D, Sibilia J. Etk/BMX, a Btk family tyrosine kinase, and Mal contribute to the cross-talk between MyD88 and FAK pathways. J Immunol. 2008;180:3485-3491. [PubMed] |
| 50. | Fukata M, Michelsen KS, Eri R, Thomas LS, Hu B, Lukasek K, Nast CC, Lechago J, Xu R, Naiki Y. Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis. Am J Physiol Gastrointest Liver Physiol. 2005;288:G1055-G1065. [PubMed] [DOI] |
| 51. | Reber SO, Obermeier F, Straub RH, Falk W, Neumann ID. Chronic intermittent psychosocial stress (social defeat/overcrowding) in mice increases the severity of an acute DSS-induced colitis and impairs regeneration. Endocrinology. 2006;147:4968-4976. [PubMed] [DOI] |
| 52. | Fan J, Malik AB. Toll-like receptor-4 (TLR4) signaling augments chemokine-induced neutrophil migration by modulating cell surface expression of chemokine receptors. Nat Med. 2003;9:315-321. [PubMed] [DOI] |
| 53. | Mihaescu A, Santen S, Jeppsson B, Thorlacius H. p38 Mitogen-activated protein kinase signalling regulates vascular inflammation and epithelial barrier dysfunction in an experimental model of radiation-induced colitis. Br J Surg. 2010;97:226-234. [PubMed] [DOI] |
| 54. | Li Y, Cao C, Jia W, Yu L, Mo M, Wang Q, Huang Y, Lim JM, Ishihara M, Wells L. Structure of the F-spondin domain of mindin, an integrin ligand and pattern recognition molecule. EMBO J. 2009;28:286-297. [PubMed] [DOI] |
| 55. | Guleng B, Lian YM, Ren JL. Mindin is upregulated during colitis and may activate NF-kappaB in a TLR-9 mediated manner. World J Gastroenterol. 2010;16:1070-1075. [PubMed] [DOI] |