TLR ligands induce synergistic interferon-β and interferon-λ1 gene expression in human monocyte-derived dendritic cells
TLR ligands induce synergistic interferon-β and interferon-λ1 gene expression in human monocyte-derived dendritic cells
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DOI：
10.1016/j.molimm.2010.10.005
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发表时间：
2011-01-01
影响因子：
3.6
通讯作者：
Julkunen, Ilkka
中科院分区：
文献类型：
--
作者：
Makela, Sanna M.;Osterlund, Pamela;Julkunen, Ilkka
Toll样受体（TLR）是先天免疫系统的模式识别受体，其识别各种病原体相关分子。TLR配体是免疫细胞的有效活化剂，并且某些TLR配体具有诱导促炎细胞因子产生的协同能力。在本研究中，我们分析了TLR 3，TLR 4和TLR 7/8配体在人单核细胞衍生的树突状细胞（moDCs）中I型和III型干扰素（IFN）基因表达中的潜在协同作用。我们表明，用TLR 7/8配体R848与TLR 3或TLR 4配体（分别为聚I：C或LPS）一起刺激moDC导致IFN-β和IFN-λ 1 mRNA的协同表达。I型IFN的中和以及刺激前的IFN引发表明IFN依赖性正反馈回路至少部分地负责协同作用的机制。TLR 3，尤其是TLR 7的表达增强，这两者都在I型IFN的调节下，与IFN-β和IFN-λ 1基因的协同TLR配体依赖性诱导相关。NF-κ B、PI 3激酶和MAP激酶通路参与TLR配体诱导的IFN基因表达，药理学信号传导抑制剂证实了这一点。数据表明，IFN有助于在用多种TLR配体刺激的人DC中TLR依赖性基因活化。(C)2010爱思唯尔有限公司保留所有权利。
Toll-like receptors (TLRs) are pattern-recognition receptors of the innate immune system that recognize various pathogen-associated molecules. TLR ligands are potent activators of immune cells and certain TLR ligands have a synergistic ability to induce the production of pro-inflammatory cytokines. In the present study we have analyzed the potential synergy between TLR3, TLR4 and TLR7/8 ligands in type I and type III interferon (IFN) gene expression in human monocyte-derived dendritic cells (moDCs). We show that stimulation of moDCs with TLR7/8 ligand R848 together with TLR3 or TLR4 ligands, polyI:C or LPS, respectively, leads to a synergistic expression of IFN-beta and IFN-lambda 1 mRNAs. Neutralization of type I IFNs as well as IFN priming prior to stimulation suggest that IFN-dependent positive feedback loop is at least partly responsible for the mechanism of synergy. Enhanced expression of TLR3 and especially TLR7, which are both under the regulation of type I IFNs, correlated to synergistic TLR ligand-dependent induction of IFN-beta and IFN-lambda 1 genes. NF-kappa B, PI3 kinase and MAP kinase pathways were involved in TLR ligand-induced IFN gene expression as evidenced by pharmacological signaling inhibitors. The data indicates that IFNs contribute to TLR-dependent gene activation in human DCs stimulated with multiple TLR ligands. (C) 2010 Elsevier Ltd. All rights reserved.