Multiple signaling pathways contribute to synergistic TLR ligand-dependent cytokine gene expression in human monocyte-derived macrophages and dendritic cells
Multiple signaling pathways contribute to synergistic TLR ligand-dependent cytokine gene expression in human monocyte-derived macrophages and dendritic cells
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DOI：
10.1189/jlb.0808503
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发表时间：
2009-04-01
影响因子：
5.5
通讯作者：
Julkunen, Ilkka
中科院分区：
文献类型：
--
作者：
Makela, Sanna M.;Strengell, Mari;Julkunen, Ilkka
TLR是识别病原体相关结构的先天免疫受体。配体与不同TLR的结合可以以协同方式诱导促炎细胞因子的产生。我们分析了TLR配体刺激的人单核细胞衍生的巨噬细胞和树突状细胞（moDCs）中协同作用的分子机制。用TLR 8配体与TLR 3或TLR 4配体一起刺激moDC导致协同的IL-6、IL-10、IL-12和TNF-α mRNA表达和细胞因子产生。DNA结合分析显示，TLR 3和TLR 8刺激诱导多种IFN调节因子（IRF）和STAT转录因子与moDCs和巨噬细胞中IL-12 p35基因启动子IFN刺激的反应元件结合，但具有不同的结合特征和动力学。我们还证明，NF-κ B B，MAPKs和PI-3 K通路在TLR诱导的细胞因子基因表达中具有重要作用，因为这些信号通路的药理学抑制剂抑制TLR 3，TLR 4和TLR 8配体诱导的细胞因子mRNA表达和蛋白质产生。特别地，在NF-κ B、MAPK p38和PI-3 K修饰物处理的moDC中，协同IL-12 p70产生被完全消除。我们的数据表明，TLR依赖的，协同的细胞因子基因表达的结果从增强的激活和NF-κ B，IRF，MAPK，PI-3 K，STAT信号通路之间的合作。J. Leukoc. 85：664-672; 2009.
TLRs are innate immune receptors that recognize pathogen-associated structures. Binding of ligands to different TLRs can induce the production of proinflammatory cytokines in a synergistic manner. We have analyzed the molecular mechanisms of synergy in TLR ligand-stimulated human monocyte-derived macrophages and dendritic cells (moDCs). Stimulation of moDCs with the TLR8 ligand together with the TLR3 or TLR4 ligand led to synergistic IL-6, IL-10, IL-12, and TNF-alpha mRNA expression and cytokine production. DNA-binding assays showed that TLR3 and TLR8 stimulation induced binding of multiple IFN regulatory factor (IRF) and STAT transcription factors to the IL-12p35 gene promoter IFN-stimulated response element in moDCs and macrophages but with different binding profiles and kinetics. We also demonstrate that NF-kappa B, MAPKs and PI-3K pathways have an important role in TLR-induced cytokine gene expression, as pharmacological inhibitors of these signaling pathways inhibited TLR3, TLR4, and TLR8 ligand-induced cytokine mRNA expression and protein production. Especially, synergistic IL-12p70 production was abolished completely in NF-kappa B, MAPK p38, and PI-3K inhibitor-treated moDCs. Our data suggest that TLR-dependent, synergistic cytokine gene expression results from enhanced activation and cooperation among NF-kappa B, IRF, MAPK, PI-3K, and STAT signaling pathways. J. Leukoc. Biol. 85: 664-672; 2009.