Selective expression of type IIFN genes in human dendritic cells infected with Mycobacterium tuberculosis
Selective expression of type IIFN genes in human dendritic cells infected with Mycobacterium tuberculosis
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DOI：
10.4049/jimmunol.169.1.366
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发表时间：
2002-07-01
影响因子：
4.4
通讯作者：
Coccia, EM
中科院分区：
文献类型：
--
作者：
Remoli, ME;Giacomini, E;Coccia, EM
I型IFN调节免疫应答的不同方面，诱导细胞介导的免疫。我们最近发现，树突状细胞（DC）感染结核分枝杆菌（Mtb）诱导IFN-α。在这项工作中，我们已经监测了快速诱导IFN-β，然后延迟生产的IFN-α 1和/或-α 13亚型。Mtb感染快速激活NF-κ B复合物并刺激IFN调节因子（IRF）-3的磷酸化，已知这些事件在病毒感染中诱导IFN-β表达。反过来，IFN-β的自分泌产生诱导IFN刺激的基因，这些基因在其启动子中含有激活的STAT的结合位点。在DC中通过STAT活化诱导的IFN刺激的基因中，有IRF-1和IRF-7。IRF-1的表达似乎依赖于NF-κ B和STAT-1的顺序激活。一旦表达，IRF-1可以进一步刺激IFN-β的转录。IRF-7的诱导也通过磷酸化STAT-1和STAT-2的结合在转录水平上调节，形成IFN刺激的基因因子-3复合物。反过来，IRF-1和IRF-7的表达似乎是IFN-α 1/13基因延迟诱导所必需的。虽然相关的，我们的研究结果强烈支持结核分枝杆菌感染的DC分子事件级联的存在。感染后，组成型表达的NF-κ B和IRF-3被激活，可能有助于IFN-β的快速表达。反过来，IFN-β诱导的IRF-1和IRF-7可能合作诱导IFN-α 1/13，如果感染持续，这些因素被激活。
Type I IFN regulates different aspects of the immune response, inducing a cell-mediated immunity. We have recently shown that the infection of dendritic cells (DC) with Mycobacterium tuberculosis (Mtb) induces IFN-alpha. In this work we have monitored a rapid induction of IFN-beta followed by the delayed production of the IFN-alpha1 and/or -alpha13 subtypes. The Mtb infection rapidly activates the NF-kappaB complex and stimulates the phosphorylation of IFN regulatory factor (IRF)-3, events known to induce IFN-beta expression in viral infection. In turn, the autocrine production of IFN-beta induces the IFN-stimulated genes that contain binding sites for activated STATs in their promoters. Among the IFN-stimulated genes induced in DC through STAT activation are IRF-1 and IRF-7. The expression of IRF-1 appears to be dependent on the sequential activation of NF-kappaB and STAT-1. Once expressed, IRF-1 may further stimulate the transcription of IFN-beta. Induction of IRF-7 is also regulated at the transcriptional level through the binding of phosphorylated STAT-1 and STAT-2, forming the IFN-stimulated gene factor-3 complex. In turn, the IRF-1 and IRF-7 expression appears to be required for the delayed induction of the IFN-alpha1/13 genes. Although correlative, our results strongly support the existence of a cascade of molecular events in Mtb-infected DC. Upon infection, constitutively expressed NF-kappaB and IRF-3 are activated and likely contribute to the rapid IFN-beta expression. In turn, IFN-beta-induced IRF-1 and IRF-7 may cooperate toward induction of IFN-alpha1/13 if infection persists and these factors are activated.