Innate immune induction of the adaptive immune response
Innate immune induction of the adaptive immune response
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DOI：
10.1101/sqb.1999.64.429
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发表时间：
1999-01-01
期刊：
影响因子：
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通讯作者：
Janeway, CA
中科院分区：
文献类型：
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作者：
Medzhitov, R;Janeway, CA
PRR。能够诱导基因表达的PRRs，我们称之为信号PRRs，直到最近才被发现，并且哺乳动物白细胞介素-1（IL-1）受体（IL-1 R）和果蝇Toll受体信号通路之间的同源性已经提出了关于其性质的第一条线索。两种受体均激活NF-κB转录因子，并共享同源胞质结构域（Toll/IL-1 R或TIR结构域）。我们对含有TIR结构域的新型蛋白质的研究鉴定出了果蝇Toll蛋白的人类同源物（Medzhitov等，1997）。那时我们知道dToll是果蝇对真菌感染的先天免疫应答的重要组成部分，涉及抗真菌肽drosomycin的诱导产生（Lemaitre et al. 1996）。在我们用TLR 4的显性活性形式进行的第一个实验中，我们用小鼠CD 4的胞外域替换了胞外域，包括含有四个半半胱氨酸残基的大部分质膜区域。这去除了四个半半胱氨酸残基中的三个，并使基因具有显性活性，就像突变四个半胱氨酸残基中的任何一个都会使dToll具有显性活性一样，如突变体Toll 10 B（Belvin和安德森1996）。当我们用这种构建体转染人巨噬细胞系THP-1时，我们观察到几个基因被诱导，包括共刺激分子B7。1、B7。2，促炎细胞因子IL-1β、IL-6和IL-12 p40，以及趋化因子IL-8，其是中性粒细胞引诱剂。我们还观察到，显性活性TLR 4激活转录因子NF-κB，为我们提供了关于其信号传导途径性质的有力线索（Medzhitov et al. 1997）。
PRRs. The PRRs that are able to induce gene expression, which we refer to as signaling PRRs, were unknown until recently, and the first clues as to their nature had been suggested by the homology between mammalian interleukin-1 (IL-1) receptor (IL-1R) and Drosophila Toll receptor signaling pathways. Both receptors activate the NF-κB transcription factor and share a homologous cytoplasmic domain (Toll/IL-1R or TIR domain). Our search for novel proteins containing a TIR domain resulted in identification of a human homolog of the Drosophila Toll protein (Medzhitov et al. 1997). We knew by then that dToll was an essential part of the Drosophila innate immune response to fungal infection, involving the induced production of the antifungal peptide drosomycin (Lemaitre et al. 1996). In the first experiments we performed with a dominant active form of TLR4, we replaced the ectodomain, including much of the juxtamembrane region that contains four half-cysteine residues, with the ectodomain of mouse CD4. This removed three of the four half-cysteine residues and made the gene dominantly active, much as mutating any one of the four half-cysteine residues renders dToll dominantly active, as in the mutant Toll 10B (Belvin and Anderson 1996). When we transfected the human macrophage cell line THP-1 with this construct, we observed that several genes were induced, including the costimulatory molecules B7. 1 and B7. 2, the proinflammatory cytokines IL-1β, IL-6, and IL-12 p40, and the chemokine IL-8 which is a neutrophil attractant. We also observed that the dominant active TLR4 activated the transcription factor NF-κB, giving us a strong clue as to the nature of its signaling pathway (Medzhitov et al. 1997).