An essential role for IFN-β in the induction of IFN-stimulated gene expression by LPS in macrophages.
An essential role for IFN-β in the induction of IFN-stimulated gene expression by LPS in macrophages.
复制标题
IFN-β 在巨噬细胞中 LPS 诱导 IFN 刺激的基因表达中发挥重要作用。
DOI：
10.1189/jlb.2a0414-191r
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发表时间：
2014-10
影响因子：
5.5
通讯作者：
Donnelly RP
中科院分区：
文献类型：
--
作者：
Sheikh F;Dickensheets H;Gamero AM;Vogel SN;Donnelly RP
干扰素-β介导巨噬细胞中脂多糖对ISGF 3的激活和干扰素刺激基因的诱导。TLR激动剂如LPS和poly（I：C）诱导巨噬细胞表达I型IFN，如IFN-α和IFN-β。为了研究IFN-β在LPS诱导ISG中的作用，我们比较了LPS诱导WT和Ifnb 1 −/−小鼠骨髓源性巨噬细胞中ISGF 3活性和ISG表达的能力。我们发现，LPS处理激活ISGF 3并诱导ISG如Oas 1，Mx 1，Ddx 58（RIG-I）和Ifih 1（MDA 5）在WT巨噬细胞中表达，但在Ifnb 1 −/−小鼠或Ifnar 1 −/−小鼠衍生的巨噬细胞中不表达。LPS不能诱导Ifnb 1 −/−巨噬细胞中ISGF 3和ISG表达的活化与LPS不能诱导这些细胞中STAT 1和-2的活化相关。与这些发现一致，LPS处理也未能诱导来自Stat 2 KO小鼠的骨髓源性巨噬细胞中的ISG表达。虽然在Ifnb 1 −/−和Ifnar 1 −/−巨噬细胞中，LPS对ISGF 3的激活和对ISG表达的诱导被废除，但NF-κ B B的激活和NF-κ B应答基因（如TNF-α）和IL-1 B（IL-1β）的诱导不受IFN-β或IFN-αR1基因缺失的影响。这些发现表明，LPS诱导ISGF 3活性和ISG表达主要依赖于IFN-β的中间产物和通过I型IFN受体的自分泌信号传导。
Interferon-β mediates the activation of ISGF3 and induction of interferon-stimulated genes, by lipopolysaccharide in macrophages. TLR agonists such as LPS and poly(I:C) induce expression of type I IFNs, such as IFN-α and -β, by macrophages. To examine the role of IFN-β in the induction of ISGs by LPS, we compared the ability of LPS to induce ISGF3 activity and ISG expression in bone marrow–derived macrophages from WT and Ifnb1−/− mice. We found that LPS treatment activated ISGF3 and induced expression of ISGs such as Oas1, Mx1, Ddx58 (RIG-I), and Ifih1 (MDA5) in WT macrophages, but not in macrophages derived from Ifnb1−/− mice or Ifnar1−/− mice. The inability of LPS to induce activation of ISGF3 and ISG expression in Ifnb1−/− macrophages correlated with the failure of LPS to induce activation of STAT1 and -2 in these cells. Consistent with these findings, LPS treatment also failed to induce ISG expression in bone marrow–derived macrophages from Stat2 KO mice. Although activation of ISGF3 and induction of ISG expression by LPS was abrogated in Ifnb1−/− and Ifnar1−/− macrophages, activation of NF-κB and induction of NF-κB-responsive genes, such as Tnf (TNF-α) and Il1b (IL-1β), were not affected by deletion of either the IFN-β or IFN-αR1 genes. These findings demonstrate that induction of ISGF3 activity and ISG expression by LPS is critically dependent on intermediate production of IFN-β and autocrine signaling through type I IFN receptors.