Peptidoglycan Enhances IL-6 Production in Human Synovial Fibroblasts via TLR2 Receptor, Focal Adhesion Kinase, Akt, and AP-1-Dependent Pathway
Peptidoglycan Enhances IL-6 Production in Human Synovial Fibroblasts via TLR2 Receptor, Focal Adhesion Kinase, Akt, and AP-1-Dependent Pathway
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DOI：
10.4049/jimmunol.0802826
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发表时间：
2009-08-15
影响因子：
4.4
通讯作者：
Tang, Chih-Hsin
中科院分区：
文献类型：
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作者：
Chiu, Yung-Cheng;Lin, Ching-Yuang;Tang, Chih-Hsin
肽聚糖（PGN）是革兰氏阳性菌细胞壁的主要成分，可激活宿主先天免疫系统，诱导细胞因子和趋化因子的释放。我们研究了类风湿性关节炎滑膜成纤维细胞中PGN刺激IL-6产生的信号通路。PGN引起IL-6产生的浓度和时间依赖性增加。TLR2小干扰RNA和核苷酸结合寡聚化结构域2小干扰RNA可减弱pgnn介导的IL-6的产生。PI3K抑制剂（Ly294002和wortmannin）、Akt抑制剂和AP-1抑制剂（丹参酮HA）预处理也抑制了PGN的增强作用。PGN增加了局灶黏附激酶（FAK）、PI3K和Akt的磷酸化。用PGN刺激类风湿关节炎滑膜成纤维细胞可增加磷酸化c-Jun在细胞核中的积累、AP-1荧光素酶活性以及c-Jun与IL-6启动子上AP-1元件的结合。PGN介导磷酸化的c-Jun在细胞核中的积累增加，AP-1荧光素酶活性增加，并且c-Jun与AP-1元件的结合被Ly294002、Akt抑制剂和FAK突变体抑制。我们的研究结果表明，PGN通过TLR2受体/FAK/PI3K/Akt和AP-1信号通路增加人滑膜成纤维细胞中IL-6的产生。中华免疫学杂志，2009,18(3):785- 792。
Peptidoglycan (PGN), the major component of the cell wall of Gram-positive bacteria, activates the innate immune system of the host and induces the release of cytokines and chemokines. We investigated the signaling pathway involved in IL-6 production stimulated by PGN in rheumatoid arthritis synovial fibroblasts. PGN caused concentration- and time-dependent increases in IL-6 production. PGN-mediated IL-6 production was attenuated by TLR2 small interfering RNA and nucleotide-binding oligomerization domain 2 small interfering RNA. Pretreatment with PI3K inhibitor (Ly294002 and wortmannin), Akt inhibitor, and AP-1 inhibitor (tanshinone HA) also inhibited the potentiating action of PGN. PGN increased the focal adhesion kinase (FAK), PI3K, and Akt phosphorylation. Stimulation of rheumatoid arthritis synovial fibroblast cells with PGN increased the accumulation of phosphorylated c-Jun in the nucleus, AP-1-luciferase activity, and c-Jun binding to the AP-1 element on the IL-6 promoter. PGN mediated an increase in the accumulation of phosphorylated c-Jun in the nucleus, AP-1-luciferase activity, and c-Jun binding to AP-1 element was inhibited by Ly294002, Akt inhibitor, and FAK mutant. Our results suggest that PGN increased IL-6 production in human synovial fibroblasts via the TLR2 receptor/FAK/PI3K/Akt and AP-1 signaling pathway. The Journal of Immunology, 2009,183: 2785-2792.