TLR4在妊娠异常终止中的作用机制和研究进展

中国畜牧兽医

TLR4在妊娠异常终止中的作用机制和研究进展

张谊¹，何自标²，陈晨²，鲜红³，张明²

1. 西昌学院动物科学学院，四川西昌 615013；2.四川农业大学动物科技学院，四川雅安 625014；3.成都市妇女儿童医院生殖不孕研究所，四川成都 610015

收稿日期:2014-01-19 出版日期:2014-07-20 发布日期:2014-08-21
通讯作者: 张明（1975—），男，博士，教授，研究方向：动物繁殖生物技术。E-mail：zhm3000@163.com
作者简介:张谊（1976—），男，四川人，硕士，副教授，研究方向：动物遗传育种与繁殖。
基金资助:
国家人力资源部和社会保障部留学人员科技活动项目：LPS诱导下TLRs和抗炎症细胞因子在母兔生殖器官中的表达模式。

Research Advance and Functional Mechanism on TLR4 in Anomalous Termination of Pregnancy

ZHANG Yi¹, HE Zi-biao², CHEN Chen², XIAN Hong³, ZHANG Ming²

1. School of Animal Science, Xichang College, Xichang 615013, China；2.College of Animal Sci & Tech, Sichuan Agricultural University, Ya’an 625014, China； 3.The Department of Human Reproduction and Sterility, Chengdu Maternity & Children Hospital, Chengdu 610015, China

Received:2014-01-19 Online:2014-07-20 Published:2014-08-21

摘要/Abstract

摘要： Toll样受体（toll-like receptors，TLRs）作为一种病原模式识别受体在免疫反应中起着重要的作用。TLR4是最早发现的TLRs成员，它是革兰氏阴性菌胞壁成分脂多糖（lipopolysaccharide, LPS）的识别受体。LPS与TLR4在胞外结合后，通过MyD88依赖和非依赖途径引起炎症反应。TLR4在生殖道炎症反应中具有重要作用，临床上可通过对利用TLR4信号转导通路的阻断来获得治疗效果。作者概述了TLR4的分子结构、组织表达和细胞内信号转导，以及在生殖系统病变状态下的表达，在此基础上提出了TLR4在生殖临床医学应用上可能的意义。

关键词:

先天性免疫; Toll样受体4; 脂多糖; 信号转导; 妊娠终止

Abstract: Toll-like receptors(TLRs) as the member of pathogen pattern recognition receptors play important roles in the immune response. TLR4 is the first discovered member of the TLRs, which is the recognition receptors of lipopolysaccharide(LPS), the component from cell wall of Gram-negative bacteria. The binding of LPS and TLR4 in the extracellular induce inflammation by the MyD88-dependent or independent ways. TLR4 plays a pivotal role in the genital tract inflammation, and in clinical treatment，that intracellular signal pathway of TLR4 is blocked by antagonists or drug can achieve therapeutic effects. In the article, molecular structure, tissue expression profiles and intracellular signal transduction were described, and the relationship between its expression and reproductive system disease were stated. After that, we propose some suggestions and outlooks in reproductive clinical medicine by regulating the signal pathway of TLR4.

Key words:

innate immune；tollmso-bidi-font-family: 宋体" lang="EN-US">-like receptor 4；lipopolysaccharide；signal transduction；pregnant termination

张谊，何自标，陈晨，鲜红，张明. TLR4在妊娠异常终止中的作用机制和研究进展[J]. 中国畜牧兽医.

ZHANG Yi, HE Zi-biao, CHEN Chen, XIAN Hong, ZHANG Ming. Research Advance and Functional Mechanism on TLR4 in Anomalous Termination of Pregnancy[J]. China Animal Husbandry & Veterinary Medicine.

参考文献

1 王玉,李晓玫,王海燕. 白介素-1 β通过JNK/p38信号转导通路调控肾系膜细胞表达α-平滑肌肌动蛋白［J］. 生理学报, 2002, 54(3): 244～250.
2 王纪文,曲鹏,姜华,等. 抑制NF-κB对Toll样受体4在Goldblatt鼠左室心肌中表达的影响［J］. 高血压杂志, 2005, 18(7): 427～431.
3 陈仁金,王珍珍,杨章平，等. 中国荷斯坦牛Toll样受体4基因的遗传多态性与体细胞评分的关联分析［J］.中国畜牧兽医, 2013, 40(11): 134～138.
4 高庆贞,吕家驹,张辉,等. 阻断MAPK通路对前列腺癌细胞增殖的影响［J］. 山东大学学报（医学版）, 2006, 44(5): 501～507.
5 Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity［J］. Cell, 2006, 124(4): 783～801.
6 Boehkov V N, Kadl A, Huber J, et al. Protective role of phospholipid oxidation products in endotoxin-induced tissue damage［J］.Nature, 2002, 419(6902):77～81.
7 Burrough E R, DiVerde K D, Sahin O, et al. Expression of toll-like receptors 2 and 4 in subplacental trophoblasts from guinea pigs(Cavia porcellus) following infection with Campylobacter jejuni［J］. Vet Pathol, 2011, 48(2): 381～2388.
8 Clark D A, Chaouat G, Banwatt D, et al. Ecology of danger-dependent cytokine-boosted spontaneous abortion in the CBA×DBA/2 mouse model: Ⅱ. Fecal LPS levels in colonies with different basal abortion rates［J］. Am J Reprod Immunol, 2008, 60(6): 529～533.
9 Deng F, Han F, Wu C. Expression and immune effect of toll-like receptor 4 in human trophoblast cells［J］. Medical Sciences, 2009, 29(3): 359～362.
10 Ferwerda B, McCall M B, Verheijen K, et al. Functional consequences of toll-like receptor 4 polymorphisms［J］. Mol Med, 2008, 14(5～6): 346～352.
11 Friebe A, Douglas A J, Solano E,et al. Neutralization of LPS or blockage of TLR4 signaling prevents stress-triggered fetal loss in murine pregnancy［J］. Journal of Molecular Medicine, 2011, 89(7): 689～699.
12 Gonzalez J M, Xu H, Ofori E, et al. Toll-like receptors in the uterus, cervix, and placenta: Is pregnancy an immunosuppressed state［J］. Am J Obstet Gynecol, 2007, 197(3): 296.
13 Haziot A, Ferrero E, Kntgen F, et al. Resistance to endotoxin shock and reduced dissemination of gram-negative bacteria in CD14-deficient mice［J］. Immunity, 1996, 4(4): 407～414.
14 Haziot A, Lin X Y, Zhang F, et al. Cutting edge: The induction of acute phase proteins by lipopolysaccharide uses a novel pathway that is CD14-independent［J］. The Journal of Immunology, 1998, 160(6): 2570～2572.
15 Ishihara S, Rumi M, Cava C O, et al. Therapeutic targeting of toll-like receptors in gastrointestinal inflammation［J］. Curr Pharm Des, 2006, 12(32):4215～4228.
16 Jin M S, Lee J O. Structures of the toll-like receptor family and its ligand complexes［J］. Immunity, 2008, 29(2): 182～191.
17 Kubo H, Ishizawa K. Comment on cutting edge: TLR4 deficiency confers susceptibility to lethal oxidant lung injury［J］. The Journal of Immunology, 2006, 176(7): 3856～3857.
18 Leon C G, Tory R, Jia J, et al. Discovery and development of toll-like receptor 4(TLR4) antagonists: A new paradigm for treating sepsis and other diseases［J］. Pharm Res, 2008, 25(8): 1751～1761.
19 Li T, Hu J, Thomas J A, et al. Differential induction of apoptosis by LPS and taxol in monocytic cells［J］. Mol Immunol, 2005, 42(9): 1049～1055.
20 Liu H, Redline R W, Han Y W. Fusobacterium nucleatum induces fetal death in mice via stimulation of TLR4-mediated placental inflammatory response［J］. J Immunol, 2007, 179(4): 2501～2508.
21 Ma Y, Krikun G, Abrahams V M, et al. Cell type-specific expression and function of toll-like receptor 2 and 4 in human placenta: Implications in fetal infection［J］. Placenta, 2007, 28(10): 1024～1031.
22 Mulla M J, Brosens J J, Chamley L W, et al. Antiphospholipid antibodies induce a pro-inflammatory response in first trimester trophoblast via the TLR4/ MyD88 pathway［J］. Am J Reprod Immunol, 2009, 62(2): 96～111.
23 Newton R, Holden N S, Catley M C, et al. Repression of inflammatory gene expression in human pulmonary epithelial cells by small-molecule IκB kinase inhibitors［J］. Pharmacol Exp ther, 2007, 321(2): 734～742.
24 Ozoe A, Isobe N, Yoshimura Y. Expression of toll-like receptors(TLRs) and TLR4 response to lipopolysaccharide in hen oviduct［J］. J Elsevier, 2009, 127(3～4):259～268.
25 Palsson E M, O’Neill L A. Signal transduction by the lipopolysaccharide receptor, toll-like receptor-4［J］. Immunology, 2004, 113(2): 153～162.
26 Romagne F. Current and future drugs targeting one class of innate immunity receptors: The toll-like receptors［J］. Drug Discov Today, 2007, 12(1～2): 80～87.
27 Riley J K, Nelson D M. Toll-like receptors in pregnancy disorders and placental dysfunction［J］. Clin Rev Allergy Immunol, 2010, 39(3):185～193.
28 Sheedy F J, O’Neill L A. The Troll in Toll: Mal and TRAM as bridges for TLR2 and TLR4 signaling［J］. Leukoc Biol, 2007, 82(2): 196～203.
29 Sumitomo M, Tachibana M, Ozu C，et al. Induction of apoptosis of cytokine-producing bladder cancer cells by adenovirus-mediated I kappa B alpha overexpression［J］.Hum Gene Ther, 1999, 10(1): 37～48.
30 Wang H, Hirsch E. Bacterially-induced preterm labor and regulation of prostaglandin-metabolizing enzyme expression in mice: The role of toll-like receptor 4［J］. Biology of reproduction, 2003, 69(6): 1957～1963.
31 Watanabe S, Kumazawa Y, Inoue J. Liposomal lipopolysaccharide initiates TRIF-dependent signaling pathway independent of CD14［J］. PLoS One, 2013, 8(4): e60078.
32 Yamamoto M, Sato S, Hemmi H，et al. Role of adaptor TRIF in the MyD88-independent toll-like recepotor signaling pathway［J］. Science, 2003, 301(5633): 640～643.
33 Yu L, Wang L, Chen S. Dual character of toll-like receptor signaling: Pro-tumorigenic effects and anti-tumor functions［J］. Biochim Biophys Acta, 2013, 1835(2): 144～154.
34 Zhang M, Nii T, Isobe N，et al. Expression of toll-like receptors and effects of lipopolysaccharide on the expression of proinflammatory cytokines and chemokine in the testis and epididymis of roosters［J］. Poultry Science, 2012, 91(8):1997～2003.

[1]	陆瑞, 盛辉, 郭妍岩, 张羽欣, 姚大为, 郭晓飞, 阮维斌, 张效生. 脂多糖免疫应激研究进展[J]. 中国畜牧兽医, 2025, 52(2): 946-958.
[2]	常欣欣, 黄鑫, 范港, 杨佳欣, 张伟伟, 杨清竹, 田哲. 大麻二酚对脂多糖诱导的小鼠乳腺上皮细胞炎症反应和凋亡的抑制作用[J]. 中国畜牧兽医, 2025, 52(1): 60-69.
[3]	许浩天, 于月通, 李静, 马志远, 杨彬, 王泽坤, 陀海欣, 齐萌. 脂多糖与钙离子共处理的牛乳腺上皮细胞miRNA表达谱的比较分析[J]. 中国畜牧兽医, 2024, 51(9): 4066-4079.
[4]	方人来, 陈敬宜, 李杭林, 刘晴, 陈奇, 胡庭俊. 苍朴乌梅散对脂多糖致腹泻小鼠的保护作用[J]. 中国畜牧兽医, 2024, 51(9): 4143-4152.
[5]	何家宇, 杨茗淇, 伍娇, 杨宇, 姚欢, 易金娥, 孔丽. C57BL/6小鼠炎症性肠病模型的建立与指标评价[J]. 中国畜牧兽医, 2024, 51(9): 4153-4163.
[6]	张晓涵, 孙岚源, 宋转, 侯永清, 吴涛. 诃子提取物对脂多糖刺激肉鸡肠道和肝脏损伤的影响[J]. 中国畜牧兽医, 2024, 51(8): 3267-3278.
[7]	胡明霞, 邓艳萍, 何永芸, 姚玥, 莫晓丹, 黄安, 杨秀芬. 桂郁金醇提物对脂多糖致小鼠肺损伤的保护作用研究[J]. 中国畜牧兽医, 2024, 51(8): 3652-3661.
[8]	冯晓梦, 高超, 陶新磊, 李小方, 吕晓萍, 高雪丽, 赵一, 李亚楠, 刘超男. HIF-1α信号通路对脂多糖诱导鸡巨噬细胞炎症的调节作用研究[J]. 中国畜牧兽医, 2024, 51(5): 2071-2080.
[9]	张杰, 李思敏, 宋晓雨, 王旭, 许玉珉, 段建平, 马云枝, 赵敏. 补肾通腑方对脂多糖诱导的认知障碍模型大鼠学习记忆能力的影响及作用机制研究[J]. 中国畜牧兽医, 2024, 51(5): 2110-2121.
[10]	宝华, 户春丽, 安彦昊, 张春华, 马燕芬. 表没食子儿茶素没食子酸酯对脂多糖诱导的奶牛乳腺上皮细胞炎性损伤和凋亡的干预作用[J]. 中国畜牧兽医, 2024, 51(5): 2122-2131.
[11]	刘应昆, 郭玮, 付增宇, 孙萌, 李昊佳, 周海柱. 阿魏酸对脂多糖应激的吉林白鹅生长性能和肠道抗氧化指标的影响[J]. 中国畜牧兽医, 2024, 51(2): 521-529.
[12]	余梓榆, 张冰琪, 蔡远荣, 洪龙胜, 李婉雁, 曹楠, 黄运茂, 许丹宁, 田允波, 陈文斌, 李冰心. LPS诱导马冈鹅法氏囊损伤相关基因的筛选[J]. 中国畜牧兽医, 2023, 50(7): 2639-2650.
[13]	钟粤韵, 杨舒展, 陈非玥, 陆智儿, 李冰心, 李婉雁, 田允波, 黄运茂, 许丹宁, 曹楠. LPS通过ROS/p38/MAPK信号通路对鹅胚肝细胞凋亡的影响[J]. 中国畜牧兽医, 2023, 50(6): 2224-2232.
[14]	邵永斌, 郑一闯, 张竞怡, 魏琳颖, 田勇, 孙国结, 刘雨然, 罗燕, 谷新利. 益母草碱对LPS诱导小鼠子宫内膜炎的抗炎作用研究[J]. 中国畜牧兽医, 2023, 50(5): 2149-2155.
[15]	秦蓉芬, 贾琼, 于雷涛, 李佳敏, 迟志端, 范瑞文. STAT3纳米抗体的制备与功能鉴定[J]. 中国畜牧兽医, 2023, 50(3): 1118-1128.