Interleukin-18 secretion and Th1-like cytokine responses in human peripheral blood mononuclear cells under the influence of the toll-like receptor-5 ligand flagellin
Interleukin-18 secretion and Th1-like cytokine responses in human peripheral blood mononuclear cells under the influence of the toll-like receptor-5 ligand flagellin
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DOI：
10.1111/j.1462-5822.2005.00621.x
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发表时间：
2006-02-01
影响因子：
3.4
通讯作者：
Mühl, H
中科院分区：
文献类型：
--
作者：
Bachmann, M;Horn, K;Mühl, H
鞭毛蛋白（Flagellin）是运动细菌鞭毛的主要蛋白质组分，被鉴定为Toll样受体（TLR）-5的配体。尽管其对上皮细胞的影响已被详细研究，但鞭毛蛋白对人外周血单核细胞（PBMC）的激活仅部分表征。通过使用慕尼黑沙门氏菌的重组蛋白，我们证实了核因子-κ B活化和白细胞介素（IL）-8的产生检测到的鞭毛蛋白的促炎性质。本研究的目的是阐明鞭毛蛋白在PBMC中对IL-18和Th 1样细胞因子应答的影响。我们报道，病理生理相关浓度的鞭毛蛋白增加了THP-1单核细胞、PBMC和全血经尼日利亚菌素刺激或ATP介导的P2 X（7）嘌呤能受体激活后成熟IL-18的释放。IL-18/IL-12/干扰素-γ（IFN γ）途径的其他关键功能被鞭毛蛋白上调。鞭毛蛋白与IL-12协同产生IFN-γ并增加干扰素诱导蛋白-10的分泌，干扰素诱导蛋白-10是一种CXC趋化因子，是产生Th 1型应答的关键。相反，IL-18结合蛋白和IL-4均不受影响。综上所述，本数据首次证明，在脓毒症期间在血液隔室中可检测到的浓度下的鞭毛蛋白有效地增强了IL-18/IL-12/IFN γ途径，从而增强了PBMC中的Th 1样细胞因子应答。
Flagellin is the major protein component of the flagella from motile bacteria and was identified as the ligand for toll-like receptor (TLR)-5. Whereas its effects on epithelial cells have been studied in detail, activation of human peripheral blood mononuclear cells (PBMC) by flagellin is characterized only partially. By using the recombinant protein of Salmonella muenchen we confirm the proinflammatory nature of flagellin as detected by nuclear factor-kappa B activation and interleukin (IL)-8 production. Aim of the current study was to elucidate in PBMC effects of flagellin on IL-18 and Th1-like cytokine responses. We report that flagellin in pathophysiologically relevant concentrations augmented release of mature IL-18 by THP-1 monocytes, PBMC, and whole blood stimulated with nigericin or by ATP-mediated P2X(7) purinergic receptor activation. Further key functions of the IL-18/IL-12/interferon-gamma (IFN gamma) pathway were upregulated by flagellin. Flagellin synergized with IL-12 for production of IFN-gamma and augmented secretion of interferon-inducible protein-10, a CXC-chemokine that is key to the generation of Th1-type responses. In contrast, neither IL-18-binding protein nor IL-4 was affected. Taken together, the present data demonstrate for the first time that flagellin at concentrations that are detectable in the blood compartment during sepsis efficiently enhances the IL-18/IL-12/IFN gamma pathway and thus Th1-like cytokine responses in PBMC.