Sphingosine-1-Phosphate Receptor 2 Regulates Proinflammatory Cytokine Production and Osteoclastogenesis.
Sphingosine-1-Phosphate Receptor 2 Regulates Proinflammatory Cytokine Production and Osteoclastogenesis.
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DOI：
10.1371/journal.pone.0156303
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Yu H
中科院分区：
文献类型：
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作者：
Yu H
鞘氨醇-1-磷酸受体2（S1 PR 2）与Gi、Gq和G12/13组蛋白偶联，其调节一系列细胞信号传导途径并影响对多种刺激的免疫应答。在这项研究中，我们证明了通过特异性S1 PR 2 shRNA慢病毒载体敲低S1 PR 2可显著抑制口腔病原体伴放线菌聚集杆菌（Aggregatibacteractinomycetemcomitans，A.与对照相比，在小鼠骨髓来源的单核细胞和巨噬细胞（Bacteria）中，放线菌共生菌（Actinomycetemcomitans）。此外，通过S1 PR 2 shRNA慢病毒载体敲低S1 PR 2可抑制A.伴放线菌此外，与对照组相比，用S1 PR 2 shRNA慢病毒载体处理的骨髓细胞抑制RANKL诱导的破骨细胞生成。S1 PR 2 shRNA抑制骨髓细胞中6种破骨细胞生成因子的mRNA水平，包括活化T细胞胞浆钙调神经磷酸酶依赖性核因子1（NFATc 1）、组织蛋白酶K（Ctsk）、酸性磷酸酶5（Acp 5）、破骨细胞相关受体（Oscar）、树突状细胞特异性跨膜蛋白（Dcstamp）和破骨细胞刺激性跨膜蛋白（Ocstamp）。我们的结论是，S1 PR 2在调节促炎细胞因子的产生和破骨细胞生成中起着至关重要的作用。阻断S1 PR 2信号可能是治疗炎症性骨丢失疾病的一种新型治疗策略。
Sphingosine-1-phosphate receptor 2 (S1PR2) couples with the Gi, Gq, and G12/13 group of proteins, which modulate an array of cellular signaling pathways and affect immune responses to multiple stimuli. In this study, we demonstrated that knockdown of S1PR2 by a specific S1PR2 shRNA lentiviral vector significantly inhibited IL-1β, IL-6, and TNF-α protein levels induced by oral pathogen Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) in murine bone marrow-derived monocytes and macrophages (BMMs) compared with controls. In addition, knockdown of S1PR2 by the S1PR2 shRNA lentiviral vector suppressed p-PI3K, p-ERK, p-JNK, p-p38, and p-NF-κBp65 protein expressions induced by A. actinomycetemcomitans. Furthermore, bone marrow cells treated with the S1PR2 shRNA lentiviral vector inhibited osteoclastogenesis induced by RANKL compared with controls. The S1PR2 shRNA suppressed the mRNA levels of six osteoclastogenic factors including nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 1 (NFATc1), cathepsin K (Ctsk), acid phosphatase 5 (Acp5), osteoclast-associated receptor (Oscar), dendritic cells specific transmembrane protein (Dcstamp), and osteoclast stimulatory transmembrane protein (Ocstamp) in bone marrow cells. We conclude that S1PR2 plays an essential role in modulating proinflammatory cytokine production and osteoclastogenesis. Blocking S1PR2 signaling might be a novel therapeutic strategy to treat inflammatory bone loss diseases.