Acute Serum Amyloid A Induces Migration, Angiogenesis, and Inflammation in Synovial Cells In Vitro and in a Human Rheumatoid Arthritis/SCID Mouse Chimera Model
Acute Serum Amyloid A Induces Migration, Angiogenesis, and Inflammation in Synovial Cells In Vitro and in a Human Rheumatoid Arthritis/SCID Mouse Chimera Model
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DOI：
10.4049/jimmunol.0902941
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发表时间：
2010-06-01
影响因子：
4.4
通讯作者：
Fearon, Ursula
中科院分区：
文献类型：
--
作者：
Connolly, Mary;Marrelli, Alessandra;Fearon, Ursula
血清淀粉样蛋白A （A- saa）是一种具有细胞因子样特性的急性期蛋白，在炎症部位表达。本研究在体外、离体和体内研究了A-SAA对类风湿关节炎（RA）细胞和全组织外植体的趋化因子调控的迁移和血管生成的影响。实时荧光定量PCR和酶联免疫吸附测定A-SAA水平。ELISA法检测RA滑膜成纤维细胞、人微血管内皮细胞和RA滑膜外植体中IL-8和MCP-1的表达。使用抗mcp -1/抗il -8或不加抗mcp -1/抗il -8的跨井白细胞/单核细胞迁移试验、侵袭试验和粘附试验检测中性粒细胞跨内皮细胞迁移、细胞粘附、侵袭和迁移。使用特异性抑制剂和Western blotting检测NF-kappa B。采用RA滑膜/SCID小鼠嵌合体模型，观察A-SAA对RA滑膜/SCID小鼠体内细胞迁移、增殖和血管生成的影响。RA患者中A-SAA高表达（p < 0.05）。a - saa诱导趋化因子表达呈时间和剂量依赖性（p < 0.05）。阻断抗清除率受体B类成员1和脂素A4 （A-SAA受体）可显著降低RA滑膜组织外体趋化因子的表达（p < 0.05）。A-SAA诱导细胞侵袭、中性粒细胞-跨内皮细胞迁移、单核细胞迁移和粘附（均p < 0.05），这些作用被抗il- 8或抗mcp -1阻断。α - saa诱导的趋化因子表达通过NF-kappa B介导（p < 0.05）。最后，在RA滑膜/SCID小鼠嵌合体模型中，我们首次在体内证明了A-SAA直接诱导单核细胞从小鼠循环向RA滑膜移植物迁移，滑膜细胞增殖和血管生成（p < 0.05）。A-SAA促进细胞迁移机制和血管生成，对RA的发病至关重要。中华免疫学杂志，2010,18(4):627 - 637。
Serum amyloid A (A-SAA), an acute-phase protein with cytokine-like properties, is expressed at sites of inflammation. This study investigated the effects of A-SAA on chemokine-regulated migration and angiogenesis using rheumatoid arthritis (RA) cells and whole-tissue explants in vitro, ex vivo, and in vivo. A-SAA levels were measured by real-time PCR and ELISA. IL-8 and MCP-1 expression was examined in RA synovial fibroblasts, human microvascular endothelial cells, and RA synovial explants by ELISA. Neutrophil transendothelial cell migration, cell adhesion, invasion, and migration were examined using transwell leukocyte/monocyte migration assays, invasion assays, and adhesion assays with or without anti-MCP-1/anti-IL-8. NF-kappa B was examined using a specific inhibitor and Western blotting. An RA synovial/SCID mouse chimera model was used to examine the effects of A-SAA on cell migration, proliferation, and angiogenesis in vivo. High expression of A-SAA was demonstrated in RA patients (p < 0.05). A-SAA induced chemokine expression in a time-and dose-dependent manner (p < 0.05). Blockade with anti-scavenger receptor class B member 1 and lipoxin A4 (A-SAA receptors) significantly reduced chemokine expression in RA synovial tissue explants (p < 0.05). A-SAA induced cell invasion, neutrophil-transendothelial cell migration, monocyte migration, and adhesion (all p < 0.05), effects that were blocked by anti-IL-8 or anti-MCP-1. A-SAA-induced chemokine expression was mediated through NF-kappa B in RA explants (p < 0.05). Finally, in the RA synovial/SCID mouse chimera model, we demonstrated for the first time in vivo that A-SAA directly induces monocyte migration from the murine circulation into RA synovial grafts, synovial cell proliferation, and angiogenesis (p < 0.05). A-SAA promotes cell migrational mechanisms and angiogenesis critical to RA pathogenesis. The Journal of Immunology, 2010, 184: 6427-6437.