Mmm-derived lipid-associated membrane proteins activate IL-1β production through the NF-κB pathway via TLR2, MyD88, and IRAK4.
Mmm-derived lipid-associated membrane proteins activate IL-1β production through the NF-κB pathway via TLR2, MyD88, and IRAK4.
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Mmm 衍生的脂质相关膜蛋白通过 TLR2、MyD88 和 IRAK4 通过 NF-kappa B 途径激活 IL-1 β 的产生
DOI：
10.1038/s41598-017-04729-y
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发表时间：
2017-06-28
影响因子：
4.6
通讯作者：
Xin J
中科院分区：
文献类型：
--
作者：
Wang Y;Wang Q;Li Y;Chen Y;Shao J;Nick N;Li C;Xin J
丝状支原体(Mmm)是引起犊牛肺炎、中耳炎和关节炎的病原体。其发病机制部分归因于过度的免疫反应。MMM来源的脂质相关膜蛋白(LAMP)是宿主天然免疫系统的有效诱导剂，但作为病原体的MMM来源的LAMP与Toll样受体(Toll-like Receptor，TLRs)以及激活炎症的信号通路和核因子-κB之间的相互作用尚未完全阐明。在此，我们分析了MMM来源的LAMP刺激的胚胎牛肺细胞中IL-1β的表达动力学，发现MMM来源的LAMP诱导IL-1β的表达。亚细胞定位分析显示，Mmm衍生灯刺激EBL细胞后，NF-κB p65亚基发生核移位。此外，一种特异的抑制实验表明，核因子-κB是MMM来源的LAMP诱导的IL-1β表达所必需的。此外，在LAMP刺激过程中，TLR2、髓系分化主要反应基因88(MyD88)和IL-1受体相关蛋白4(IRAK4)的过表达增加了IL-1β的表达，而TLR2中和抗体在LAMP刺激过程中降低了IL-1β的表达。此外，LAPs还抑制了显性阴性MyD88和IRAK4变异体转染后IL-1β的表达。这些结果表明，MMM来源的LAMP通过TLR2、MyD88和IRAK4通过NF-βB途径激活IL-1κ的产生。
Mycoplasma mycoides subsp.mycoides (Mmm) is a pathogen that causes pneumonia, otitis media, and arthritis in young calves. Its pathogenesis is attributed in part to excessive immune responses. Mmm-derived lipid-associated membrane proteins (LAMPs) are potent inducers of the host innate immune system; however, interactions between Mmm-derived LAMPs as pathogenic agents, toll-like receptors (TLRs), and the signaling pathways responsible for activating inflammation and nuclear factor (NF)-κB have not been fully elucidated. Here, we analyzed the expression kinetics of interleukin (IL)-1β in Mmm-derived LAMP-stimulated embryonic bovine lung (EBL) cells and found that Mmm-derived LAMPs induced IL-1β expression. Subcellular localization analysis revealed the nuclear translocation of the NF-κB p65 subunit after EBL cells were stimulated with Mmm-derived LAMPs. Furthermore, a specific inhibitor assay demonstrated that NF-κB is required for Mmm-derived LAMP-induced IL-1β expression. Additionally, overexpression of TLR2, myeloid differentiation primary response gene 88 (MyD88), and IL-1 receptor-associated kinase 4 (IRAK4) increased IL-1β expression during LAMP stimulation, and TLR2-neutralizing antibodies reduced IL-1β expression in EBL cells during LAMP stimulation. Furthermore, LAMPs inhibited IL-1β expression following transfection with dominant-negative MyD88 and IRAK4 variants. These results suggested that Mmm-derived LAMPs activate IL-1β production through the NF-κB pathway via TLR2, MyD88, and IRAK4.