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首页> 外文期刊>Infection and immunity >Toll-Like Receptor 2 Mediates Cellular Activation by the B Subunits of Type II Heat-Labile Enterotoxins
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Toll-Like Receptor 2 Mediates Cellular Activation by the B Subunits of Type II Heat-Labile Enterotoxins

机译：类似Toll样受体2通过II型不耐热肠毒素的B亚基介导细胞活化

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The type II heat-labile enterotoxins (LT-IIa and LT-IIb) of Escherichia coli have an AB5 subunit structure similar to that of cholera toxin (CT) and other type I enterotoxins, despite significant differences in the amino acid sequences of their B subunits and different ganglioside receptor specificities. LT-II holotoxins and their nontoxic B subunits display unique properties as immunological adjuvants distinct from those of CT and its B subunits. In contrast to type II holotoxins, the corresponding pentameric B subunits, LT-IIaB and LT-IIbB, stimulated cytokine release in both human and mouse cells dependent upon Toll-like receptor 2 (TLR2). Induction of interleukin-1β (IL-1β), IL-6, IL-8, or tumor necrosis factor alpha in human THP-1 cells by LT-IIaB or LT-IIbB was inhibited by anti-TLR2 but not by anti-TLR4 antibody. Furthermore, transient expression of TLR1 and TLR2 in human embryonic kidney 293 cells resulted in activation of a nuclear factor-κB-dependent luciferase gene in response to LT-IIaB or LT-IIbB. Moreover, peritoneal macrophages from TLR2-deficient mice failed to respond to LT-IIaB or LT-IIbB, in contrast to wild-type or TLR4-deficient cells. These results demonstrate that besides their established binding to gangliosides, the B subunits of type II enterotoxins also interact with TLR2. Although a ganglioside-nonbinding mutant (T34I) of LT-IIaB effectively induced cytokine release, a phenotypically similar point mutation (T13I) in LT-IIbB abrogated cytokine induction, suggesting a variable requirement for gangliosides as coreceptors in TLR2 agonist activity. TLR2-dependent activation of mononuclear cells by type II enterotoxin B subunits appears to be a novel mechanism whereby these molecules may exert their immunomodulatory and adjuvant activities.
机译：大肠埃希菌的II型不耐热肠毒素（LT-IIa和LT-IIb）的AB 5 亚基结构类似于霍乱毒素（CT）和其他I型肠毒素，尽管其B亚基的氨基酸序列存在明显差异，并且神经节苷脂受体的特异性不同。作为免疫佐剂，LT-II全毒素及其无毒的B亚基表现出独特的特性，不同于CT及其B亚基。与II型全毒素相反，依赖于Toll样受体2（TLR2），相应的五聚体B亚基LT-IIaB和LT-IIbB刺激了人和小鼠细胞中的细胞因子释放。 TL-IIaB或LT-IIbB诱导人THP-1细胞中白介素1β（IL-1β），IL-6，IL-8或肿瘤坏死因子α被抗TLR2抑制，但不受抗TLR4抑制抗体。此外，TLR1和TLR2在人类胚胎肾293细胞中的瞬时表达导致响应LT-IIaB或LT-IIbB的核因子-κB依赖的荧光素酶基因的激活。此外，与野生型或TLR4缺陷细胞相比，TLR2缺陷小鼠的腹膜巨噬细胞不能对LT-IIaB或LT-IIbB作出反应。这些结果表明，除了已确定的与神经节苷脂的结合外，II型肠毒素的B亚基还与TLR2相互作用。尽管LT-IIaB的神经节苷脂非结合突变体（T34I）有效地诱导了细胞因子的释放，但LT-IIbB的表型相似点突变（T13I）废除了细胞因子的诱导，这表明神经节苷脂作为TLR2激动剂活性的共受体需要不同的要求。 II型肠毒素B亚基对TLR2依赖性单核细胞的激活似乎是一种新颖的机制，由此这些分子可发挥其免疫调节和佐剂活性。

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