Innate immunity at the mucosal surface: Role of toll-like receptor 3 and toll-like receptor 9 in cervical epithelial cell responses to microbial pathogens
Innate immunity at the mucosal surface: Role of toll-like receptor 3 and toll-like receptor 9 in cervical epithelial cell responses to microbial pathogens
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DOI：
10.1095/biolreprod.105.048629
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发表时间：
2006-05-01
影响因子：
3.6
通讯作者：
Ingalls, RR
中科院分区：
文献类型：
--
作者：
Andersen, JM;Al-Khairy, D;Ingalls, RR
Toll样受体(Toll-like Receptor，TLR)是一类模式识别受体家族，它识别包括核酸在内的多种病原体共有的不同分子模式。例如，TLR9识别细菌和一些病毒核酸中常见的未甲基化脱氧胞苷-磷酸-脱氧鸟苷(CpG)二核苷酸，而TLR3识别双链RNA，TLR7/TLR8识别病毒复制过程中发现的单链RNA。我们感兴趣的是TLR3、TLR9以及相关的TLR9家族成员TLR7/TLR8是否在女性生殖道下段粘膜上皮表面发挥抗病毒免疫防御作用。我们研究了宫颈上皮细胞，发现它们表达TLR3、TLR9和TLR7的mRNA，但只有TLR8的微弱信号。TLR3和TLR9蛋白在细胞内表达。当上皮细胞与多聚肌苷多胞苷和CpG寡核苷酸孵育时，我们观察到白介素8的分泌呈剂量依赖性的上调。然而，细胞对多种TLR7/TLR8配体没有反应。多聚肌苷多胞酸也能诱导干扰素-β和趋化因子C-C基序配体5的产生，而CpG DNA不能。人工合成的寡核苷酸只有在B类序列的响应下才能激活细胞，并且需要人类特有的CpG基序的存在。此外，对CpG寡核苷酸的反应可被氯喹抑制，这表明内体成熟是必需的。这些结果表明，粘膜上皮细胞表达功能性的TLR3和TLR9，提示这些受体在感染病毒和细菌病原体的过程中对下部雌性生殖道的促炎细胞因子和抗病毒环境起着调节作用。
Toll-like receptors (TLRs) are a family of pattern recognition receptors that recognize distinct molecular patterns shared by a broad range of pathogens, including nucleic acids. TLR9, for example, recognizes unmethylated deoxycytidyl-phosphate-deoxyguanosine (CpG) dinucleotides that are common in bacterial and some viral nucleic acids, whereas TLR3 recognizes double-stranded RNA and TLR7/TLR8 recognize single-stranded RNA, which would be found during viral replication. We were interested in whether TLR3, TLR9, and the related TLR9 family members TLR7/TLR8 might play a role in antiviral immune defense at the mucosal epithelial surface of the lower female reproductive tract. We studied cervical epithelial cells and found that they expressed mRNA for TLR3, TLR9, and TLR7, but had only a weak signal for TLR8. For TLR3 and TLR9, protein expression was confirmed to be intracellular. When epithelial cells were incubated with polyinosine-polycytidylic acid and CpG oligodinucleotides, we observed dose-dependent upregulation of interleukin-8 secretion. However, cells failed to respond to a variety of TLR7/TLR8 ligands. Polyinosine-polycytidylic acid also induced production of interferon-beta and chemokine C-C motif ligand 5, whereas CpG DNA did not. Cell activation by synthetic oligodinucleotides occurred only in response to the B class sequences, and required the presence of human-specific CpG motifs. In addition, responses to CpG oligodinucleotides could be inhibited by chloroquine, demonstrating the requirement for endosomal maturation. These data demonstrate that mucosal epithelial cells express functional TLR3 and TLR9, and suggest that these receptors play a role in regulating the proinflammatory cytokine and antiviral environment of the lower female reproductive tract during infection with viral and bacterial pathogens.