Bradykinin-induced IL-6 expression through bradykinin B2 receptor, phosphollipase C, protein kinase Cδ and NF-κB pathway in human synovial fibroblasts
Bradykinin-induced IL-6 expression through bradykinin B2 receptor, phosphollipase C, protein kinase Cδ and NF-κB pathway in human synovial fibroblasts
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DOI：
10.1016/j.molimm.2008.06.007
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发表时间：
2008-08-01
影响因子：
3.6
通讯作者：
Tang, Chih-Hsin
中科院分区：
文献类型：
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作者：
Lee, Cheng-Hung;Shieh, Dong-Chen;Tang, Chih-Hsin
缓激肽 (BK) 是一种炎症介质，在严重损伤和炎症性疾病区域表现出升高的水平。它已被证明可以在类风湿性关节炎的炎症反应中诱导白细胞介素 6 (IL-6) 的表达。我们研究了滑膜成纤维细胞中 BK 引起的 IL-6 产生所涉及的信号通路。 BK 导致 IL-6 产量呈浓度和时间依赖性增加。通过使用 BK 受体的药理学抑制剂或基因抑制，siRNA 揭示 B2 而不是 131 BK 受体参与 BK 介导的 IL-6 上调。磷脂酶 C 抑制剂 (U73122)、蛋白激酶 C δ 抑制剂 (rottlerin)、NF-kappa B 抑制剂 (PDTC) I kappa B 蛋白酶抑制剂 (TPCK) 和 NF-kappa B 抑制肽可减弱 BK 介导的 IL-6 产生。使用 BK 激活的 I kappa B 激酶 α/β (IKK α/β)、I kappa B α 磷酸化、I kappa B α 降解、Ser(276) 上的 p65 磷酸化、p65 和 p50 从细胞质到细胞核的易位以及 kappa B-荧光素酶活性刺激滑膜成纤维细胞。 BK 介导 IKK α/β 和 Iκβ α 磷酸化、κ B-荧光素酶活性以及 p65 和 p50 与 NF-κ B 元件的结合增加，并被 B2 BK 受体拮抗剂 (HOE140)、U73122 和 rottlerin 抑制。我们的结果表明，BK 通过 B2 BK 受体/Pl-PLC/PKC delta/和 NF-kappa B 信号通路增加滑膜成纤维细胞中 IL-6 的产生。 (C) 2008 Elsevier Ltd. 保留所有权利。
Bradykinin (BK) is an inflammatory mediator, and shows elevated levels in regions of severe injury and inflammatory diseases. It has been shown to induce interleukin-6 (IL-6) expression in inflammatory responses in rheumatoid arthritis. We investigated the signaling pathway involved in IL-6 production caused by BK in synovial fibroblasts. BK caused concentration- and time-dependent increases in IL-6 production. By using pharmacological inhibitors or genetic inhibition of the BK receptor, siRNA revealed that B2 but not 131 BK receptors are involved in BK-mediated up-regulation of IL-6. BK-mediated IL-6 production was attenuated by phospholipase C inhibitor (U73122), protein kinase C delta inhibitor (rottlerin), NF-kappa B inhibitor (PDTC) I kappa B protease inhibitor (TPCK) and NF-kappa B inhibitor peptide. Stimulation of synovial fibroblasts with BK activated I kappa B kinase alpha/beta (IKK alpha/beta), I kappa B alpha phosphorylation, I kappa B alpha degradation, p65 phosphorylation at Ser(276), p65 and p50 translocation from the cytosol to the nucleus and kappa B-luciferase activity. BK mediated an increase of IKK alpha/beta and I kappa beta alpha phosphorylation, kappa B-luciferase activity and p65 and p50 binding to the NF-kappa B element was inhibited by B2 BK receptor antagonist (HOE140), U73122 and rottlerin. Our results suggest that BK increased IL-6 production in synovial fibroblasts via the B2 BK receptor/Pl-PLC/PKC delta/and NF-kappa B signaling pathway. (C) 2008 Elsevier Ltd. All rights reserved.