Department of Vaccination and Immune Protection, National Institute for Heath and Welfare, PO Box 30, FI-00271 Helsinki, Finland.
Mol Immunol. 2011 Jan;48(4):505-15. doi: 10.1016/j.molimm.2010.10.005. Epub 2010 Oct 30.
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-β and IFN-λ1 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-β and IFN-λ1 genes. NF-κB, 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.
Toll 样受体 (TLRs) 是先天免疫系统的模式识别受体，可识别各种病原体相关分子。TLR 配体是免疫细胞的有效激活剂，某些 TLR 配体具有协同诱导促炎细胞因子产生的能力。在本研究中，我们分析了 TLR3、TLR4 和 TLR7/8 配体在 I 型和 III 型干扰素 (IFN) 基因表达中的协同作用。我们发现，TLR7/8 配体 R848 与 TLR3 或 TLR4 配体聚肌苷酸或 LPS 分别刺激 moDCs 可导致 IFN-β 和 IFN-λ1 mRNA 的协同表达。I 型 IFNs 的中和以及 IFN 的预先刺激表明，IFN 依赖性正反馈环至少部分负责协同作用的机制。增强表达 TLR3，特别是 TLR7，这两者都受到 I 型 IFNs 的调节，与 TLR 配体依赖性诱导 IFN-β 和 IFN-λ1 基因的协同作用相关。NF-κB、PI3 激酶和 MAP 激酶途径参与 TLR 配体诱导的 IFN 基因表达，这可通过药理学信号转导抑制剂证明。数据表明，IFNs 有助于多种 TLR 配体刺激的人类 DC 中 TLR 依赖性基因激活。
