O'Mahony D Shane, Pham Uyenvy, Iyer Ramesh, Hawn Thomas R, Liles W Conrad
Departments of Medicine, University of Washington, Seattle, WA 98195, USA.
Int J Med Sci. 2008 Jan 4;5(1):1-8. doi: 10.7150/ijms.5.1.
Human Toll-like receptors (TLRs) comprise a family of proteins that recognizes pathogen-associated molecular patterns (PAMPs) and initiates host innate immune responses. Neutrophils, monocytes, and macrophages are critical cellular components of the human innate immune system. Proinflammatory cytokines, such as granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), and interferon-gamma (IFN-gamma), have been shown to up-regulate microbicidal activity in these effector cells of innate immunity. Currently, the cellular and molecular mechanisms responsible for these effects are not completely understood. We hypothesized that these cytokines may up-regulate TLR expression as a mechanism to facilitate microbial recognition and augment the innate immune response. Using quantitative realtime rt-PCR technology, we examined constitutive expression of TLR2, TLR4, TLR5, and TLR9 mRNA and the effects of G-CSF, GM-CSF, M-CSF, and IFN-gamma on TLR mRNA expression in purified populations of normal human neutrophils, monocytes, and monocyte-derived macrophages. Relative constitutive expression of TLR2, TLR4, and TLR9 was similar in neutrophils and monocytes. Constitutive expression of TLR5 was less in neutrophils compared to monocytes. Constitutive expression of TLR4 was greater and that of TLR9 lower in monocyte-derived macrophages compared to monocytes. Of the cytokines examined, IFN-gamma and GM-CSF caused the greatest effects on TLR expression. IFN- gamma up-regulated TLR2 and TLR4 in neutrophils and monocytes. GM-CSF up-regulated expression of TLR2 and TLR4 in neutrophils and TLR2 in monocytes. TLR5 was down-regulated by inflammatory cytokines in monocytes. These results suggest a potential role for IFN- gamma and/or GM-CSF as therapeutic immunomodulators of the host defense to infection.
人类 Toll 样受体（TLR）是一类蛋白质家族，可识别病原体相关分子模式（PAMP）并启动宿主固有免疫反应。中性粒细胞、单核细胞和巨噬细胞是人类固有免疫系统的关键细胞成分。促炎细胞因子，如粒细胞集落刺激因子（G-CSF）、粒细胞-巨噬细胞集落刺激因子（GM-CSF）、巨噬细胞集落刺激因子（M-CSF）和干扰素-γ（IFN-γ），已被证明可上调这些固有免疫效应细胞中的杀菌活性。目前，导致这些效应的细胞和分子机制尚未完全明确。我们推测这些细胞因子可能上调 TLR 表达，以此作为促进微生物识别和增强固有免疫反应的一种机制。我们使用定量实时 rt-PCR 技术，检测了 TLR2、TLR4、TLR5 和 TLR9 mRNA 的组成性表达，以及 G-CSF、GM-CSF、M-CSF 和 IFN-γ 对正常人中性粒细胞、单核细胞和单核细胞衍生巨噬细胞纯化群体中 TLR mRNA 表达的影响。TLR2、TLR4 和 TLR9 在中性粒细胞和单核细胞中的相对组成性表达相似。与单核细胞相比，中性粒细胞中 TLR5 的组成性表达较低。与单核细胞相比，单核细胞衍生巨噬细胞中 TLR4 的组成性表达较高，而 TLR9 的组成性表达较低。在所检测的细胞因子中，IFN-γ 和 GM-CSF 对 TLR 表达的影响最大。IFN-γ 上调中性粒细胞和单核细胞中的 TLR2 和 TLR4。GM-CSF 上调中性粒细胞中的 TLR2 和 TLR4 以及单核细胞中的 TLR2。单核细胞中的 TLR5 被炎性细胞因子下调。这些结果表明 IFN-γ 和/或 GM-CSF 作为宿主抗感染防御的治疗性免疫调节剂具有潜在作用。
