A type I interferon autocrine-paracrine loop is involved in Toll-like receptor-induced interleukin-12p70 secretion by dendritic cells.
A type I interferon autocrine-paracrine loop is involved in Toll-like receptor-induced interleukin-12p70 secretion by dendritic cells.
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I型Interferon自分泌 - 核酸环与树突状细胞的Toll样受体诱导的白介素-12p70分泌有关。
DOI：
10.1084/jem.20041964
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发表时间：
2005-05-02
影响因子：
15.3
通讯作者：
Garrone, P
中科院分区：
文献类型：
--
作者：
Gautier, G;Humbert, M;Deauvieau, F;Scuiller, M;Hiscott, J;Bates, EEM;Trinchieri, G;Caux, C;Garrone, P
树突状细胞（DC）响应于Toll样受体（TLR）活化而产生白细胞介素-12（IL-12）。两种主要TLR信号传导途径参与对病原体的应答：导致炎性细胞因子分泌（包括IL-12）的核因子-κB（NF-κB）依赖性途径和诱导I型IFN和IFN调节基因的干扰素（IFN）依赖性途径。在这里，我们表明，这两种途径合作，可能都是必要的诱导病原体的最佳反应。R-848/Resiquimod（小鼠中的TLR 7配体和人中的TLR 7/8配体）与poly（I：C）（TLR 3配体）或脂多糖（LPS; TLR 4配体）协同诱导小鼠骨髓来源的DC（BM-DC）高水平的生物活性IL-12 p70分泌和IFN-β mRNA积累。引人注目的是，在来自STAT 1 −/−和IFNAR−/−小鼠的BM-DC中，IL-12 p70而不是IL-12 p40的分泌强烈减少。在用TLR配体组合激活的IFNAR−/− BM-DC中，STAT 1酪氨酸磷酸化、IL-12 p35和IFN-β mRNA积累受到强烈抑制。使用中和性抗IFNAR 2抗体在表达人TLR 8的单核细胞衍生DC（moDC）中获得了类似的观察结果，尽管结果也指出了IFN-λ1（也称为IL-29）的可能参与。这表明TLR参与DC诱导内源性IFN，其进一步与NF-κB途径协同作用以获得最佳IL-12 p70分泌。此外，干扰素调节因子（IRF）调节moDC的分析表明，IRF 7/8在介导IRF 3-独立的I型IFN和可能的IL-12 p35合成响应TLR 7/8的作用。
Dendritic cells (DC) produce interleukin-12 (IL-12) in response to Toll-like receptor (TLR) activation. Two major TLR signaling pathways participate in the response to pathogens: the nuclear factor-κB (NF-κB)–dependent pathway leading to inflammatory cytokine secretion including IL-12 and the interferon (IFN)-dependent pathway inducing type I IFN and IFN-regulated genes. Here we show that the two pathways cooperate and are likely both necessary for inducing an optimal response to pathogens. R-848/Resiquimod (TLR7 ligand in the mouse and TLR7/8 ligand in human) synergized with poly(I:C) (TLR3 ligand) or lipopolysaccharide (LPS; TLR4 ligand) in inducing high levels of bioactive IL-12p70 secretion and IFN-β mRNA accumulation by mouse bone marrow–derived DC (BM-DC). Strikingly, IL-12p70 but not IL-12p40 secretion was strongly reduced in BM-DC from STAT1−/− and IFNAR−/− mice. STAT1 tyrosine-phosphorylation, IL-12p35, and IFN-β mRNA accumulation were strongly inhibited in IFNAR−/− BM-DC activated with the TLR ligand combinations. Similar observation were obtained in human TLR8-expressing monocyte-derived DC (moDC) using neutralizing anti-IFNAR2 antibodies, although results also pointed to a possible involvement of IFN-λ1 (also known as IL-29). This suggests that TLR engagement on DC induces endogenous IFNs that further synergize with the NF-κB pathway for optimal IL-12p70 secretion. Moreover, analysis of interferon regulatory factors (IRF) regulation in moDC suggests a role for IRF7/8 in mediating IRF3-independent type I IFN and possibly IL-12p35 synthesis in response to TLR7/8.
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影响因子：
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