Conditional signaling by Toll-like receptor 4
Conditional signaling by Toll-like receptor 4
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DOI：
10.1096/fj.04-3211fje
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发表时间：
2005-02-01
期刊：
影响因子：
4.8
通讯作者：
Platt, JL
中科院分区：
文献类型：
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作者：
Brunn, GJ;Bungum, MK;Platt, JL
通过Toll样受体4（TLR4）的信号传导被认为可启动先天性和适应性免疫应答。TLR4的信号传导通常利用分离的细胞进行研究，这些细胞可被亚纳摩尔浓度的脂多糖（LPS）激活。然而，在正常组织中，携带TLR4的细胞存在于含有大量可刺激该受体的内源性物质的微环境中。我们利用人细胞系HEK 293开发了一种体外模型系统，并利用具有正常或缺乏TLR4受体的小鼠建立了一种体内模型，以研究TLR4在这种微环境中如何发挥作用。在此我们报道，完整的细胞外基质强烈抑制通过TLR4的信号传导，并且当基质降解时，这种抑制被解除，内源性激动剂被释放。因此，从抑制中释放而非由诸如LPS等激动剂直接刺激是TLR4启动免疫应答的关键首要事件。
Signaling through Toll-like receptor 4 (TLR4) is thought to initiate innate and adaptive immune responses. Signaling of TLR4 is usually studied using isolated cells, which are activated by subnanomolar concentrations of lipopolysaccharide (LPS). However, in normal tissues, cells bearing TLR4 reside in microenvironments containing large amounts of endogenous substances that can stimulate the receptor. We developed an in vitro model system using the human cell line HEK 293 and an in vivo model using mice that have normal or that lack TLR4 receptors to study how TLR4 functions in such microenvironments. Here we report that signaling through TLR4 is strongly inhibited by intact extracellular matrix and that inhibition is abrogated and endogenous agonist(s) are liberated when the matrix is degraded. Thus, release from inhibition rather than direct stimulation by agonists such as LPS is the critical first event by which TLR4 initiates immune responses.