Resolvin D2 decreases TLR4 expression to mediate resolution in human monocytes
Resolvin D2 decreases TLR4 expression to mediate resolution in human monocytes
复制标题
DOI：
10.1096/fj.201600375r
复制
发表时间：
2016-09-01
期刊：
影响因子：
4.8
通讯作者：
Phipps, Richard P.
中科院分区：
文献类型：
--
作者：
Croasdell, Amanda;Sime, Patricia J.;Phipps, Richard P.
tlr对先天免疫至关重要，但过度激活会导致组织损伤和疾病。专门的促炎性介质（SPMs），包括resolvin D2 (RvD2)，促进炎症的主动消退。SPMs如何调节早期LPS信号，包括TLR4的激活，尚不清楚。我们用RvD2和LPS处理人THP-1单核细胞和原代人血液单核细胞，以评估TLRs的调节。通过miRNA-146a过表达和抑制来剖析rvd2介导作用的机制。我们使用细胞因子elisa、PCR、Western blot分析和流式细胞术验证了我们的研究。用0.1%乙醇（对照RvD2）和/或PBS（对照LPS）处理的细胞，以及对照microRNA模拟物和抑制剂作为对照。RvD2将lps诱导的细胞因子和TLR4在人单核细胞中的表达降低了75%。在THP-1细胞中，RvD2降低了TLR4、淋巴细胞抗原96 （MD-2）和下游信号（MyD88、TRIF和TAK1）的表达。这些作用部分通过RvD2诱导microRNA-146a介导，而RvD2的作用被microRNA-146a抑制所阻断。这些新发现揭示了RvD2降低TLR4表达和减轻lps诱导炎症的能力，为这一主要治疗研究领域的SPM活性研究提供了一个新的领域。Croasdell， A., Sime， P. J, Phipps， R. P. Resolvin D2降低TLR4表达介导人类单核细胞的溶解。
TLRs are critical for innate immunity, but excessive activation can lead to tissue damage and disease. Specialized proresolving mediators (SPMs), including resolvin D2 (RvD2), promote the active resolution of inflammation. How SPMs regulate early LPS signaling, including activation of TLR4, is unknown. We treated human THP-1 monocytic cells and primary human blood monocytes with RvD2 and LPS to evaluate modulation of TLRs. miRNA-146a overexpression and inhibition were used to dissect the mechanism of RvD2-mediated actions. We validated our studies using ELISAs for cytokines, PCR, Western blot analysis, and flow cytometry. Cells treated with 0.1% ethanol (control for RvD2) and/or PBS (control for LPS), and control microRNA mimics and inhibitors were used as controls. RvD2 reduced LPS-induced cytokines and TLR4 expression in human monocytes by up to 75%. In THP-1 cells, RvD2 reduced expression of TLR4, lymphocyte antigen 96 (MD-2), and downstream signals (MyD88, TRIF, and TAK1). These effects were partially mediated through RvD2 induction of microRNA-146a, and RvD2's actions were blocked by microRNA-146a inhibition. These new findings reveal the ability of RvD2 to reduce TLR4 expression and attenuate LPS-induced inflammation, providing a new area of SPM activity to investigate in this major area of therapeutic research.Croasdell, A., Sime, P. J., Phipps, R. P. Resolvin D2 decreases TLR4 expression to mediate resolution in human monocytes.