TLR10 Is a Negative Regulator of Both MyD88-Dependent and -Independent TLR Signaling.
TLR10 Is a Negative Regulator of Both MyD88-Dependent and -Independent TLR Signaling.
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DOI：
10.4049/jimmunol.1502599
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发表时间：
2016-05-01
期刊：
影响因子：
--
通讯作者：
Tapping RI
中科院分区：
文献类型：
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作者：
Jiang S;Li X;Hess NJ;Guan Y;Tapping RI
Toll样受体是先天免疫系统的中心成分，一旦识别细菌、真菌或病毒成分，就会激活细胞内信号，导致保护性炎症反应。在人类TLR家族的10个成员中，TLR10是唯一一个尚无已知配体或信号功能的孤儿受体。小鼠TLR10是一个被破坏的假基因，这排除了使用经典的基因敲除方法进行研究的可能性。我们在这里报道，TLR10抑制稳定转染人骨髓单核细胞U937细胞中一系列细胞因子的产生，以回应其他TLR激动剂。这种广泛的TLR抑制活性影响MyD88和TRIF介导的I-κB和MAPK激活上游的信号通路。与非转基因小鼠相比，TLR10转基因小鼠的单核细胞在其他TLR激动剂的体外血液刺激下显示出钝化的IL-6产生。腹腔注射脂多糖后，TLR10转基因小鼠血清中的肿瘤坏死因子α、IL-6和1型干扰素水平低于非转基因小鼠，但不影响内毒素诱导的感染性休克模型小鼠的存活。最后，用抗TLR10的单抗处理人单核细胞可抑制由内毒素刺激释放的促炎细胞因子。这些结果表明TLR10对TLR信号具有广泛的负调节作用，提示TLR10在体内可能具有控制免疫反应的作用。
Toll-like receptors are central components of the innate immune system which, upon recognition of bacterial, fungal or viral components, activate intracellular signals that lead to protective inflammatory responses. Among the ten-member human TLR family, TLR10 is the only remaining orphan receptor without a known ligand or signaling function. Murine TLR10 is a disrupted pseudogene, which precludes investigation using classic gene knock-out approaches. We report here that TLR10 suppressed the production of an array of cytokines in stably transfected human myelomonocytic U937 cells in response to other TLR agonists. This broad TLR suppressive activity affects both MyD88 and TRIF-mediated signaling pathways upstream of IκB and MAPK activation. Compared to non-transgenic littermate controls, monocytes of TLR10 transgenic mice exhibited blunted IL-6 production following ex vivo blood stimulation with other TLR agonists. After intraperitoneal injection of LPS, lower levels of TNFα, IL-6 and Type 1 IFN was measured in the serum of TLR10 transgenic mice, compared to non-transgenic mice, but did not affect mouse survival in an LPS-induced septic shock model. Finally, treatment of human mononuclear cells with a monoclonal anti-TLR10 antibody suppressed pro-inflammatory cytokines released by LPS stimulation. These results demonstrate that TLR10 functions as a broad negative regulator of TLR signaling and suggests TLR10 may have a role in controlling immune responses in vivo.