MyD88-dependent and MyD88-independent pathways in synergy, priming, and tolerance between TLR agonists
MyD88-dependent and MyD88-independent pathways in synergy, priming, and tolerance between TLR agonists
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DOI：
10.4049/jimmunol.178.2.1164
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发表时间：
2007-01-15
影响因子：
4.4
通讯作者：
Hellman, Judith
中科院分区：
文献类型：
--
作者：
Bagchi, Aranya;Herrup, Elizabeth A.;Hellman, Judith
TLRs感知微生物的成分，是感染过程中炎症的关键宿主介质。不同的TLR激动剂可以深刻地改变彼此的炎症效应，研究表明，接触TLR激动剂的顺序可能对感染过程中的反应产生重要影响。我们测试了TLR激动剂之间的协同、启动和耐受性遵循一种模式，该模式可以基于依赖于MyD88的(D)和不依赖于MyD88的(1)细胞内信号通路的不同参与来预测。D和I通路激动剂的联合作用在体内和体外均被量化。实验使用了几种D-特异性激动剂、I-特异性激动剂(Poly(I：C))和同时作用于D和I途径的内毒素。D-特异性激动剂包括：肽聚糖相关脂蛋白、Pam3Cys、鞭毛蛋白和CpG DNA，它们分别通过TLR2(肽聚糖相关脂蛋白和Pam3Cys)、TLR5和TLR9发挥作用。D和I激动剂在诱导小鼠体内细胞因子产生方面具有明显的协同作用。所有D-特异性激动剂在体外均能协同Poly(I：C)诱导小鼠骨髓巨噬细胞产生肿瘤坏死因子和白介素6。骨髓来源的巨噬细胞用Poly(I：C)预处理后，对随后的D-特异性激动剂产生预激反应，反之亦然，这表明细胞因子的产生增加，并增加了NF-kappa B易位。D-受体激动剂可增加内毒素诱导的干扰素-β的产生。所有D-特异性激动剂都能诱导对彼此的耐受。因此，在这里研究的条件下，D和I通路的同时和顺序激活分别引起协同和启动，耐受性是由通过相同途径作用的激动剂诱导的。
TLRs sense components of microorganisms and are critical host mediators of inflammation during infection. Different TLR agonists can profoundly alter inflammatory effects of one another, and studies suggest that the sequence of exposure to TLR agonists may importantly impact on responses during infection. We tested the hypothesis that synergy, priming, and tolerance between TLR agonists follow a pattern that can be predicted based on differential engagement of the MyD88-dependent (D) and the MyD88-independent (1) intracellular signaling pathways. Inflammatory effects of combinations of D and I pathway agonists were quantified in vivo and in vitro. Experiments used several D-specific agonists, an I-specific agonist (poly(I:C), and LPS, which acts through both the D and I pathways. D-specific agonists included: peptidoglycan-associated lipoprotein, Pam3Cys, flagellin, and CpG DNA, which act through TLR2 (peptidoglycan-associated lipoprotein and Pam3Cys), TLR5, and TLR9, respectively. D and I agonists were markedly synergistic in inducing cytokine production in vivo in mice. All of the D-specific agonists were synergistic with poly(I:C) in vitro in inducing TNF and IL-6 production by mouse bone marrow-derived macrophages. Pretreatment of bone marrow-derived macrophages with poly(I:C) led to a primed response to subsequent D-specific agonists and vice versa, as indicated by increased cytokine production, and increased NF-kappa B translocation. Pretreatment with a D-specific agonist augmented LPS-induced IFN-beta production. All D-specific agonists induced tolerance to one another. Thus, under the conditions studied here, simultaneous and sequential activation of both the D and I pathways causes synergy and priming, respectively, and tolerance is induced by agonists that act through the same pathway.