Pneumocystis-mediated IL-8 release by macrophages requires coexpression of mannose receptors and TLR2
Pneumocystis-mediated IL-8 release by macrophages requires coexpression of mannose receptors and TLR2
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DOI：
10.1189/jlb.1005580
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发表时间：
2007-01-01
影响因子：
5.5
通讯作者：
Koziel, Henry
中科院分区：
文献类型：
--
作者：
Tachado, Souvenir D.;Zhang, Jianmin;Koziel, Henry
尽管尚未确定介导 IL-8 释放的受体，但与独特的肺孢子虫 (Pc) 真菌的相互作用可促进人肺泡巨噬细胞 (AM) 释放 IL-8。 TLR2 识别真菌成分并介导宿主防御细胞因子和趋化因子的释放，但 TLR2 是否介导响应 Pc 的信号传导尚不清楚。在当前的研究中，Pc诱导人AM释放IL-8，并且用抗TLR2中和抗体对AM进行预处理减少IL-8释放。然而，在用人 TLR2 cDNA 转染的非吞噬性人胚胎肾 (HEK)293 细胞中，与 Pc 一起孵育不会诱导 IL-8 释放，而这些相同的细胞响应 TLR2 激动剂脂磷壁酸而释放 IL-8。使用小干扰RNA对AM甘露糖受体（MR；Pc的吞噬细胞受体）进行靶向基因沉默也减少了人AM中Pc介导的IL-8释放。然而，单独转染人 MR cDNA 的 HEK293 细胞不会响应 Pc 释放 IL-8。相反，共转染人TLR2和人MR cDNA的HEK293细胞响应Pc释放H,8。在人类 AM 中，Pc 促进 MR 和 TLR2 的直接相互作用，同时阻断 TLR2 和 MR 基因沉默后，IL-8 的释放显着减少，并且 IL-8 的释放部分依赖于转录因子 NF-kappa B、ERK1/2 和 JNK MAPK。这些研究表明，人 AM 介导的 Pc 介导的 IL-8 释放需要 MR 和 TLR2 的共表达，并进一步支持了这样的概念：巨噬细胞先天受体的组合相互作用提供了宿主防御细胞对感染挑战的特异性反应。
Interaction with the unique fungus Pneumocystis (Pc) promotes IL-8 release by human alveolar macrophages (AM), although the receptor(s) mediating IL-8 release have not been identified. TLR2 recognizes fungal components and mediates release of host defense cytokines and chemokines, although whether TLR2 mediates signaling in response to Pc is not known. hi the current study, Pc induced IL-8 release by human AM, and AM pretreatment with anti-TLR2 neutralizing antibody reduced IL-8 release. However, in nonphagocytic human embryonic kidney (HEK)293 cells transfected with human TLR2 cDNA, incubation with Pc did not induce IL-8 release, whereas these same cells released IL-8 in response to the TLR2 agonist lipoteichoic acid. Targeted gene silencing of AM mannose receptors (MR; phagocytic receptors for Pc) using small interfering RNA also reduced Pc-mediated IL-8 release in human AM. However, HEK293 cells transfected with human MR cDNA alone did not release IL-8 in response to Pc. In contrast, HEK293 cells cotransfected with human TLR2 and human MR cDNA released H,8 in response to Pc. In human AM, Pc promoted direct interaction of MR and TLR2, IL-8 release was reduced markedly upon simultaneous blocking of TLR2 and gene silencing of MR, and IL-8 release was dependent in part on transcription factor NF-kappa B and ERK1/2 and JNK MAPKs. These studies demonstrate that Pc-mediated IL-8 release by human AM requires the coexpression of MR and TLR2 and further supports the concept that combinatorial interactions of macrophage innate receptors provide specificity of host defense cell responses to infectious challenge.