The toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily
The toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily
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DOI：
10.1002/eji.200324238
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发表时间：
2003-11-01
影响因子：
5.4
通讯作者：
Bauer, S
中科院分区：
文献类型：
--
作者：
Heil, F;Ahmad-Nejad, P;Bauer, S
Loxoribine（7-烯丙基-7,8-二氢-8-氧代-鸟苷）在抗肿瘤反应中充当合成佐剂。在这里，我们首先证明洛索立宾通过 Toll 样受体 (TLR) 7/MyD88 依赖性信号通路选择性激活先天免疫系统的细胞。 TLR7 和 MyD88 缺陷的免疫细胞无法增殖或产生响应洛索立宾的细胞因子，并且 TLR7 缺陷细胞与鼠或人 TLR7 的基因互补赋予了反应性。随后我们表明，洛索立宾和瑞西莫德 (R-848)（TLR7 和 TLR8 的刺激物）的细胞激活依赖于内体的酸化和成熟；并将 MyD88 靶向具有溶酶体特征的囊泡结构。 TLR7 和 TLR8 的这种作用模式类似于 CpG-DNA 驱动的 TLR9 激活。因此，我们得出结论，TLR7、8 和 9 形成 TLR 家族中的一个功能亚组，可识别内体/溶酶体区室中病原体相关的分子模式。
Loxoribine (7-allyl-7,8-dihydro-8-oxo-guanosine) acts as synthetic adjuvant in anti-tumor responses. Here we first demonstrate that loxoribine activates cells of the innate immune system selectively via the Toll-like receptor (TLR) 7/MyD88-dependent signaling pathway. TLR7- and MyD88-cleficient immune cells fail to proliferate or produce cytokines in response to loxoribine, and genetic complementation of TLR7-deficient cells with murine or human TLR7 confers responsiveness. Subsequently we show that cellular activation by loxoribine and resiquimod (R-848), a stimulus for TLR7 and TLR8, depends on acidification and maturation of endosomes; and targets MyD88 to vesicular structures with lysosomal characteristics. This mode of TLR7 and TLR8 action resembles CpG-DNA-driven TLR9 activation. We thus conclude that TLR7, 8 and 9 form a functional subgroup within the TLR family that recognizes pathogen-associated molecular patterns in endosomal/lysosomal compartments.