Toll样受体和β-防御素mRNA在鼻粘膜中的表达
摘要
鼻粘膜上皮细胞在呼吸道粘膜免疫中的作用近年来越来越受到重视。人们已经认识到呼吸道上皮不再是一个单纯的物理屏障，而是一个多重身份的宿主防御的参与者。它可以同时作为感受器(sensors)、信号回路(signaling circuits)和效应分子(effectors molecules)调整和执行对微生物的炎症反应。作为呼吸道天然免疫的第一道防线。它自身可以分泌多种细胞因子和杀菌物质来参与炎症反应和宿主防御。我们以往的研究已经证明鼻粘膜上皮细胞可分泌RANTES、TNFα等细胞因子。那么鼻粘膜上皮是如何感受到微生物的侵袭，并通过怎样的机制识别病原微生物、偶联信号传导途径，以表达、产生细胞因子的呢？其机理目前仍不十分清楚。而Toll样受体（Toll-Like Receptors,TLRs）的发现给这一问题的解决带来一线曙光。
Toll样受体是近年来新发现的一个介导天然免疫的古老家族。该受体的发现最早缘于对果蝇Toll（dToll）蛋白的研究。该蛋白是果蝇细胞负责信号传递的一类跨膜受体。人们首先发现若人为敲除编码Toll蛋白的基因将导致果蝇胚胎的死亡。随即又发现在成体果蝇， Toll与配体结合能激活胞浆内的转录因子，诱导针对微生物病原体的宿主防御反应。近年来，又在植物、无脊椎
动物及脊椎动物中发现了一系列具有与Toll蛋白结构高度保守的蛋白质，且其信号激活途径也极为相似。例如：18-wheeler、Toll样受体等。这些蛋白历经数亿年演化而仍然保存下来并在先天宿主防御中发挥重要作用。因而成为近年来天然免疫研究中的热点。
目前人Toll样受体家族已确认的成员有10个（TLR1-TLR10）。它们的配体大多为病原微生物细胞壁成分（如脂多糖、磷壁酸等）。与T、B细胞抗原受体对表位高度特异的“个性化”识别相反，人及哺乳动物Toll系统识别的是病原微生物的“共性”。如革兰氏阴性菌（G-）中共有的菌壁成分脂多糖（LPS），革兰氏阳性菌（G+）中共有的肽聚糖、磷壁酸等。这一类物质，即存在于细胞壁，为多种微生物所共有的一类分子结构称之为病原相关分子模式（pathogen associated molecular patterns,PAMPs）。其化学性质多属糖脂化合物，一般不为多细胞生物所有。迄今发现的Toll样受体的配体都属PAMPs。其中TLR2识别的配体范围较广，包括：G+菌及其胞壁成分如肽聚糖、磷壁酸，分支菌属的阿拉伯甘露糖脂（LAM），螺旋体，支原体等。TLR4的配体则主要为G-菌的LPS。由此可见，TLR2和TLR4的配体已经涵盖了自然界绝大多数对人体致病的微生物类别。因此，二者在人Toll样受体家族中最为重要。TLRs主要分布于淋巴组织、白细胞、单核吞噬细胞、和树突状细胞。此外，不同的TLRs在非淋巴组织也有不同程度的表达。Wolfs等人就曾发现TLR2、TLR4在肾小管上皮细胞中表达，且在炎症状态下表达增强。这表明非免疫细胞(nonimmune cells)也能表达Toll样受体。有鉴于此，我们推测Toll样受体在鼻粘膜上皮细胞中亦有表达。因此，我们应用核酸原位杂交技术检测了TLR2、TLR4在慢性鼻窦炎患者鼻粘膜上皮细胞中的mRNA表达情况。以期探讨
Toll样受体在鼻粘膜上皮中的表达情况及其可能在鼻粘膜天然免疫中发挥的作用。
鼻息肉是临床上常见的慢性鼻黏膜炎症性疾病，也可是某些全身疾病的鼻部表现，如阿斯匹林耐受不良（Widal,s病），内源性哮喘，囊性纤维变性，Young综合征，Kartagener综合症。但病因至今不明，估计与多种因素有关，如遗传因素、免疫缺陷、解剖异常、纤毛功能障碍等。因其主要病理特征为组织水肿并伴有嗜酸性粒细胞在局部的大量浸润。故此将其与一般的感染性炎症相区别。且近来有研究表明Th2细胞因子如IL-5，IL-13在鼻息肉中过度表达。因此有观点倾向于将其列入呼吸道变应性疾病之中。但毋庸置疑，感染性因素始终是鼻息肉发病过程的重要一环。我们应用核酸原位杂交技术检测了TLR2和TLR4在鼻息肉中的表达情况。以期明确Toll样受体在鼻息肉中的分布情况及其探讨感染性因素在鼻息肉发病中发挥的作用。
防御素（defensins）是近年来天然免疫研究的另一大热点，是指一类带正电荷、富含半胱氨酸和精氨酸的低分子多肽。体外实验显示其有很强的抗细菌、真菌、病毒及细胞毒性作用。在体内则参与抵抗病原微生物的早期宿主防御反应。人类防御素根据其分子内特异的三个二硫键位置不同。可分为α、β两大类，而β-防御素有着更为广泛的细胞分布。已经证明β-防御素-1（human β–defensin-1,hBD-1）在泌尿道，女性生殖道及肺组织均有表达。β-防御素-2（hBD-2）则主要分布于表皮和气管黏膜[18],且其表达可被众多物质上调如, IL-1α、IL-1β、TNFα 、细菌、酵母及脂多糖等 。在此基础上，最新的研究表明鼻黏膜亦是β-防御素作用的靶组织之一。本研究着眼于鼻黏膜的第一道屏
障——鼻黏膜上皮层，以逆转录聚合酶链反应(reverse transcriptase-polymerase chain reaction, RT-PCR)的方法检测了慢性鼻窦炎患者及对照组的鼻黏膜上皮细胞中hBD-1和hBD-2mRNA的表达。以阐述β-防御素在上呼吸道天然免疫中的重要地位。方法：1.用核酸分子原位杂交技术检测30例慢性鼻窦炎患者和21例健康人鼻粘膜上皮细胞中TLR-2和TLR-4mRNA的表达。2.应
Epithelium of nasal mucosa, being constantly exposed to environmental pathogens, is particularly vulnerable to infection. A major function of the nasal mucosa is to provide a barrier to prevent the penetration of pathogens and other potentially noxious agents from the environment into the body. Recent studies showed that epithelium were not just a physical barrier but also dynamic host defense participants with sensors, signaling circuits, and effector molecules that coordinated and executed a graduated reaction to microbes1.As the first line of defense against invading pathogens in upper airway, epithelia secret several antimicrobial substances such as phospholipase A2, nitric oxide , and β-defensin and produce a series of cytokines such as tumor necrosis factorα(TNFα) , Interkeulin-6(IL-6), IL-8 and regulated upon activation, normal T cell expressed and secreted(RANTES) in response to inflammatory stimulations . However, little attention has been paid to the mechanism of how recognition of bacterial pathogens occurs and how the signals are transmitted into nasal epithelial cells, despite their importance in mucosal defense system. Our studies about Toll-like receptor (TLR) in the paper would be helpful for further research.
It is well known that Toll is a type I transmembrane receptor in Drosophila that is involved in dorsal-ventral patterning in larvae and in the induction of an antifungal response in adult flies . Recently, mammalian species also were found to conserve this system as the Toll-like receptors (TLR) family. In 1997, Medzhitov and colleagues were the first to characterize a human TLR, TLR4, which participates in activation of cells during both innate and adaptive immune responses. To date, ten TLR family members (TLR1-10) have been identified in the human genome11, and different TLRs appear to play crucial roles in the activation of the immune response to distinct ligands. Most of ligands for TLRs are components of bacterial cell wall. For example, the TLR4 was shown to respond to lipopolysaccharide (LPS) derived from Gram-negative bacterial cell wall. More recently, TLR2 was shown to play a parallel role in response to lipoarabinomannan (LAM), from mycobacterial species and peptidoglycan from the Gram-positive bacterial cell wall 13,14. These components of bacterial cell wall are often called pathogen-associated molecular pattens(PAMPs). TLRs are mainly expressed in lymphoid tissues such as macrophages, neutrophils, and dentritic cells. Interestingly, it has recently been shown that renal epithelial cells constitutively express both TLR2 and TLR4. This expression is upregulated by both IFN- and TNFα during renal inflammation, suggesting that nonimmune cells can express TLRs.Therefore, the present study aims to investigate the expression of TLR2 and TLR4 in the epithelial cells of human nasal mucosa, and
whether their expression are upregulated following inflammatary stimulation.
Nasal polyps is a kind of commonly encountered disease in clinical rhinology. Its etiology is still unknown and it is found in 36% of patients with aspirin intolerance,7% of those with asthma,0.1% in children,other conditions associated with nasal polyps are Young Syndrome ,alleric fungal sinusitis, and cilia dyskinetic syndrome,and Cystic fibrosis.Nasal polyps is morphologically characterized by oedema, goblet cell hypeplasia of the epithelium, thickening of the basement membrane, and of numerous leukocytes, predominantly eosinophils. it has recently been shown that Th-2 type cytokines such as IL-5,IL-13 had overexpressed in nasal polyp tissues. So nasal polyps is thinked it is different from general inflammation in upper airway for bacterial infection. However, bacterial infection still play an important role in pathogenic mechanism of nasal polyps. In this study, we examined the expression of TLR-2 and TLR-4 mRNA in nasal polyps and normal inferior turbinate by in situ hybridization .
Defensins, a major family of antimicrobial peptides found in mammals, are a recently discovered compone
Toll样受体是近年来新发现的一个介导天然免疫的古老家族。该受体的发现最早缘于对果蝇Toll（dToll）蛋白的研究。该蛋白是果蝇细胞负责信号传递的一类跨膜受体。人们首先发现若人为敲除编码Toll蛋白的基因将导致果蝇胚胎的死亡。随即又发现在成体果蝇， Toll与配体结合能激活胞浆内的转录因子，诱导针对微生物病原体的宿主防御反应。近年来，又在植物、无脊椎
动物及脊椎动物中发现了一系列具有与Toll蛋白结构高度保守的蛋白质，且其信号激活途径也极为相似。例如：18-wheeler、Toll样受体等。这些蛋白历经数亿年演化而仍然保存下来并在先天宿主防御中发挥重要作用。因而成为近年来天然免疫研究中的热点。
目前人Toll样受体家族已确认的成员有10个（TLR1-TLR10）。它们的配体大多为病原微生物细胞壁成分（如脂多糖、磷壁酸等）。与T、B细胞抗原受体对表位高度特异的“个性化”识别相反，人及哺乳动物Toll系统识别的是病原微生物的“共性”。如革兰氏阴性菌（G-）中共有的菌壁成分脂多糖（LPS），革兰氏阳性菌（G+）中共有的肽聚糖、磷壁酸等。这一类物质，即存在于细胞壁，为多种微生物所共有的一类分子结构称之为病原相关分子模式（pathogen associated molecular patterns,PAMPs）。其化学性质多属糖脂化合物，一般不为多细胞生物所有。迄今发现的Toll样受体的配体都属PAMPs。其中TLR2识别的配体范围较广，包括：G+菌及其胞壁成分如肽聚糖、磷壁酸，分支菌属的阿拉伯甘露糖脂（LAM），螺旋体，支原体等。TLR4的配体则主要为G-菌的LPS。由此可见，TLR2和TLR4的配体已经涵盖了自然界绝大多数对人体致病的微生物类别。因此，二者在人Toll样受体家族中最为重要。TLRs主要分布于淋巴组织、白细胞、单核吞噬细胞、和树突状细胞。此外，不同的TLRs在非淋巴组织也有不同程度的表达。Wolfs等人就曾发现TLR2、TLR4在肾小管上皮细胞中表达，且在炎症状态下表达增强。这表明非免疫细胞(nonimmune cells)也能表达Toll样受体。有鉴于此，我们推测Toll样受体在鼻粘膜上皮细胞中亦有表达。因此，我们应用核酸原位杂交技术检测了TLR2、TLR4在慢性鼻窦炎患者鼻粘膜上皮细胞中的mRNA表达情况。以期探讨
Toll样受体在鼻粘膜上皮中的表达情况及其可能在鼻粘膜天然免疫中发挥的作用。
鼻息肉是临床上常见的慢性鼻黏膜炎症性疾病，也可是某些全身疾病的鼻部表现，如阿斯匹林耐受不良（Widal,s病），内源性哮喘，囊性纤维变性，Young综合征，Kartagener综合症。但病因至今不明，估计与多种因素有关，如遗传因素、免疫缺陷、解剖异常、纤毛功能障碍等。因其主要病理特征为组织水肿并伴有嗜酸性粒细胞在局部的大量浸润。故此将其与一般的感染性炎症相区别。且近来有研究表明Th2细胞因子如IL-5，IL-13在鼻息肉中过度表达。因此有观点倾向于将其列入呼吸道变应性疾病之中。但毋庸置疑，感染性因素始终是鼻息肉发病过程的重要一环。我们应用核酸原位杂交技术检测了TLR2和TLR4在鼻息肉中的表达情况。以期明确Toll样受体在鼻息肉中的分布情况及其探讨感染性因素在鼻息肉发病中发挥的作用。
防御素（defensins）是近年来天然免疫研究的另一大热点，是指一类带正电荷、富含半胱氨酸和精氨酸的低分子多肽。体外实验显示其有很强的抗细菌、真菌、病毒及细胞毒性作用。在体内则参与抵抗病原微生物的早期宿主防御反应。人类防御素根据其分子内特异的三个二硫键位置不同。可分为α、β两大类，而β-防御素有着更为广泛的细胞分布。已经证明β-防御素-1（human β–defensin-1,hBD-1）在泌尿道，女性生殖道及肺组织均有表达。β-防御素-2（hBD-2）则主要分布于表皮和气管黏膜[18],且其表达可被众多物质上调如, IL-1α、IL-1β、TNFα 、细菌、酵母及脂多糖等 。在此基础上，最新的研究表明鼻黏膜亦是β-防御素作用的靶组织之一。本研究着眼于鼻黏膜的第一道屏
障——鼻黏膜上皮层，以逆转录聚合酶链反应(reverse transcriptase-polymerase chain reaction, RT-PCR)的方法检测了慢性鼻窦炎患者及对照组的鼻黏膜上皮细胞中hBD-1和hBD-2mRNA的表达。以阐述β-防御素在上呼吸道天然免疫中的重要地位。方法：1.用核酸分子原位杂交技术检测30例慢性鼻窦炎患者和21例健康人鼻粘膜上皮细胞中TLR-2和TLR-4mRNA的表达。2.应
Epithelium of nasal mucosa, being constantly exposed to environmental pathogens, is particularly vulnerable to infection. A major function of the nasal mucosa is to provide a barrier to prevent the penetration of pathogens and other potentially noxious agents from the environment into the body. Recent studies showed that epithelium were not just a physical barrier but also dynamic host defense participants with sensors, signaling circuits, and effector molecules that coordinated and executed a graduated reaction to microbes1.As the first line of defense against invading pathogens in upper airway, epithelia secret several antimicrobial substances such as phospholipase A2, nitric oxide , and β-defensin and produce a series of cytokines such as tumor necrosis factorα(TNFα) , Interkeulin-6(IL-6), IL-8 and regulated upon activation, normal T cell expressed and secreted(RANTES) in response to inflammatory stimulations . However, little attention has been paid to the mechanism of how recognition of bacterial pathogens occurs and how the signals are transmitted into nasal epithelial cells, despite their importance in mucosal defense system. Our studies about Toll-like receptor (TLR) in the paper would be helpful for further research.
It is well known that Toll is a type I transmembrane receptor in Drosophila that is involved in dorsal-ventral patterning in larvae and in the induction of an antifungal response in adult flies . Recently, mammalian species also were found to conserve this system as the Toll-like receptors (TLR) family. In 1997, Medzhitov and colleagues were the first to characterize a human TLR, TLR4, which participates in activation of cells during both innate and adaptive immune responses. To date, ten TLR family members (TLR1-10) have been identified in the human genome11, and different TLRs appear to play crucial roles in the activation of the immune response to distinct ligands. Most of ligands for TLRs are components of bacterial cell wall. For example, the TLR4 was shown to respond to lipopolysaccharide (LPS) derived from Gram-negative bacterial cell wall. More recently, TLR2 was shown to play a parallel role in response to lipoarabinomannan (LAM), from mycobacterial species and peptidoglycan from the Gram-positive bacterial cell wall 13,14. These components of bacterial cell wall are often called pathogen-associated molecular pattens(PAMPs). TLRs are mainly expressed in lymphoid tissues such as macrophages, neutrophils, and dentritic cells. Interestingly, it has recently been shown that renal epithelial cells constitutively express both TLR2 and TLR4. This expression is upregulated by both IFN- and TNFα during renal inflammation, suggesting that nonimmune cells can express TLRs.Therefore, the present study aims to investigate the expression of TLR2 and TLR4 in the epithelial cells of human nasal mucosa, and
whether their expression are upregulated following inflammatary stimulation.
Nasal polyps is a kind of commonly encountered disease in clinical rhinology. Its etiology is still unknown and it is found in 36% of patients with aspirin intolerance,7% of those with asthma,0.1% in children,other conditions associated with nasal polyps are Young Syndrome ,alleric fungal sinusitis, and cilia dyskinetic syndrome,and Cystic fibrosis.Nasal polyps is morphologically characterized by oedema, goblet cell hypeplasia of the epithelium, thickening of the basement membrane, and of numerous leukocytes, predominantly eosinophils. it has recently been shown that Th-2 type cytokines such as IL-5,IL-13 had overexpressed in nasal polyp tissues. So nasal polyps is thinked it is different from general inflammation in upper airway for bacterial infection. However, bacterial infection still play an important role in pathogenic mechanism of nasal polyps. In this study, we examined the expression of TLR-2 and TLR-4 mRNA in nasal polyps and normal inferior turbinate by in situ hybridization .
Defensins, a major family of antimicrobial peptides found in mammals, are a recently discovered compone
引文
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