Acute-phase serum amyloid a stimulation of angiogenesis, leukocyte recruitment, and matrix degradation in rheumatoid arthritis through an NF-κB-dependent signal transduction pathway
Acute-phase serum amyloid a stimulation of angiogenesis, leukocyte recruitment, and matrix degradation in rheumatoid arthritis through an NF-κB-dependent signal transduction pathway
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DOI：
10.1002/art.21518
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发表时间：
2006-01-01
影响因子：
--
通讯作者：
Fearon, U
中科院分区：
文献类型：
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作者：
Mullan, RH;Bresnihan, B;Fearon, U
客观的。研究类风湿性关节炎 (RA) 中急性时相蛋白血清淀粉样蛋白 A (A-SAA) 在调节细胞粘附分子表达、白细胞募集和血管生成中的作用。方法。使用流式细胞术和酶联免疫吸附测定技术检测 RA 成纤维样滑膜细胞 (FLS) 和人微血管内皮细胞 (HMVEC) 中细胞间粘附分子 1 (ICAM-1)、血管细胞粘附分子 I (VCAM-1) 和基质金属蛋白酶 I (MMP-1) 的表达。通过流式细胞术测定外周血单核细胞 (PBMC) 对 FLS/HMVEC 的粘附。使用博伊登趋化室和基质胶小管形成检查血管生成。使用特定的 NF-kappa B 抑制剂和蛋白质印迹研究了 NF-kappa B/I kappa B α 对 A-SAA 影响的介导。结果。 A-SAA 显着增强 ICAM-1 和 VCAM-1 的时间和剂量依赖性表达，与白细胞介素 1 β/肿瘤坏死因子 a 一样有效。 A-SAA 促进 PBMC 与 FLS 和 HMVEC 的粘附。此外，10μg/ml和50μg/ml的A-SAA分别显着增加内皮细胞管形成69％和207％。在50μg/ml和100μg/ml时，A-SAA分别使HMVEC迁移增加188+/-54%和296+/-71%(平均值+/-SEM)。 A-SAA 诱导的 VCAM-1、ICAM-1 和 MMP-1 表达可通过抑制 NF-κ B 下调。此外，A-SAA 诱导 I kappa B α 降解和 NF-kappa B 易位，表明其促炎作用部分是由 NF-kappa B 信号传导介导的。结论。我们的研究结果证明了 A-SAA 能够诱导粘附分子表达、血管生成和基质降解，这些机制是由 NF-kappa B 介导的。针对 A-SAA 及其信号通路可能代表了治疗 RA 的新治疗方法。
Objective. To examine the role of the acute-phase protein serum amyloid A (A-SAA) in regulating cell adhesion molecule expression, leukocyte recruitment, and angiogenesis in rheumatoid arthritis (RA).Methods. Intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule I (VCAM-1), and matrix metalloproteinase I (MMP-1) expression was examined in RA fibroblast-like synoviocytes (FLS) and human microvascular endothelial cells (HMVECs) using flow cytometry and enzyme-linked immunosorbent assay techniques. Peripheral blood mononuclear cell (PBMC) adhesion to FLS/HMVECs was determined by flow cytometry. Angiogenesis was examined using a Boyden chemotaxis chamber and Matrigel tubule formation. NF-kappa B/I kappa B alpha mediation of the effects of A-SAA was investigated using a specific NF-kappa B inhibitor and Western blotting.Results. A-SAA significantly enhanced the time- and dose-dependent expression of ICAM-I and VCAM-1 as effectively as interleukin-1 beta/tumor necrosis factor a. A-SAA promoted the adhesion of PBMCs to FLS and HMVECs. In addition, A-SAA at 10 mu g/ml and 50 mu g/ml significantly increased endothelial cell tube formation by 69% and 207%, respectively. At 50 mu g/ml and 100 mu g/ml, A-SAA increased HMVEC migration by 188 +/- 54% and 296 +/- 71%, respectively (mean +/- SEM). A-SAA-induced expression of VCAM-1, ICAM-1, and MMP-1 was down-regulated by NF-kappa B inhibition. Furthermore, A-SAA induced I kappa B alpha degradation and NF-kappa B translocation, suggesting that its proinflammatory effects are mediated in part by NF-kappa B signaling.Conclusion. Our findings demonstrate the ability of A-SAA to induce adhesion molecule expression, angiogenesis, and matrix degradation, mechanisms that are mediated by NF-kappa B. Targeting A-SAA and its signaling pathways may represent a new therapeutic approach in the treatment of RA.