Soluble forms of toll-like receptor (TLR)2 capable of modulating TLR2 signaling are present in human plasma and breast milk
Soluble forms of toll-like receptor (TLR)2 capable of modulating TLR2 signaling are present in human plasma and breast milk
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DOI：
10.4049/jimmunol.171.12.6680
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发表时间：
2003-12-15
影响因子：
4.4
通讯作者：
Labéta, MO
中科院分区：
文献类型：
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作者：
LeBouder, E;Rey-Nores, JE;Labéta, MO
对细菌感染的初始先天免疫应答失调可能导致败血性休克和死亡。Toll样受体（TLR）在这种先天性免疫反应中起着至关重要的作用，但控制微生物诱导的TLR触发的调节机制仍有待充分了解。因此，我们已经寻求可能调节TLR信号传导的特定调节机制。在这项研究中，我们测试了TLR2的功能活性可溶形式的可能存在。我们证明了天然可溶性形式的TLR2（sTLR2）的存在，我们表明能够调节细胞活化。我们发现，血液单核细胞组成性地释放sTLR 2，并且在细胞活化后sTLR 2释放的动力学增加。对表达人TLR2 cDNA或其c-myc标记版本的细胞的分析表明，sTLR2是由细胞内区室中TLR2蛋白的翻译后修饰引起的。此外，细胞内sTLR2库得以维持。sTLR2在母乳和血浆中天然表达。乳汁sTLR 2水平反映TLR辅助受体可溶性CD 14水平。血清中sTLR2的消耗导致细胞对细菌脂肽的反应增加。值得注意的是，结核病患者血清sTLR2较低。免疫共沉淀实验和计算分子对接研究表明，血浆和牛奶中的sTLR2和可溶性CD14之间的相互作用。这些发现表明存在调节微生物诱导的TLR触发的新型和特异性先天免疫机制，并且可能导致用于预防和/或治疗严重感染性疾病的新疗法。
Dysregulation of the initial, innate immune response to bacterial infection may lead to septic shock and death. Toll-like receptors (TLRs) play a crucial role in this innate immune response, and yet the regulatory mechanisms controlling microbial-induced TLR triggering are still to be fully understood. We have therefore sought specific regulatory mechanisms that may modulate TLR signaling. In this study, we tested for the possible existence of a functionally active soluble form of TLR2. We demonstrated the existence of natural soluble forms of TLR2 (sTLR2), which we show to be capable of modulating cell activation. We found that blood monocytes released sTLR2 constitutively and that the kinetics of sTLR2 release increased upon cell activation. Analysis of cells expressing the human TLR2 cDNA or its c-myc-tagged version indicated that sTLR2 resulted from the posttranslational modification of the TLR2 protein in an intracellular compartment. Moreover, an intracellular pool of sTLR2 is maintained. sTLR2 was found naturally expressed in breast milk and plasma. Milk sTLR2 levels mirrored those of the TLR coreceptor soluble CD14. Depletion of sTLR2 from serum resulted in an increased cellular response to bacterial lipopeptide. Notably, serum sTLR2 was lower in tuberculosis patients. Coimmunoprecipitation experiments and computational molecular docking studies showed an interaction between sTLR2 and soluble CD14 in plasma and milk. These findings suggest the existence of a novel and specific innate immune mechanism regulating microbial-induced TLR triggering, and may lead to new therapeutics for the prevention and/or treatment of severe infectious diseases.