Amelioration of rat adjuvant-induced arthritis by Met-RANTES
Amelioration of rat adjuvant-induced arthritis by Met-RANTES
复制标题
DOI：
10.1002/art.21033
复制
发表时间：
2005-06-01
影响因子：
--
通讯作者：
Koch, AE
中科院分区：
文献类型：
--
作者：
Shahrara, S;Proudfoot, AEI;Koch, AE
客观的。 CC趋化因子及其受体在炎症部位的贩运白细胞和激活中起着基本作用，从而导致类风湿关节炎的关节损伤。 Met-Rantes是一种氨基末端修饰的RANTES（CCL5）（CCL5），分别拮抗趋化因子RANTES和巨噬细胞炎性蛋白LA（MIP-1 Alpha; CCL3）与其受体CCR1和CCR5的结合。这项研究的目的是调查大鼠中的大鼠辅助诱导的关节炎（AIA）。我们使用免疫组织化学，酶联免疫吸附测定，实时逆转录 - 聚合酶链反应，蛋白质印迹分析，收养转移和趋化性，我们确定了关节炎症，骨质破坏，中性粒细胞，中性粒细胞和巨噬细胞迁移，竞争竞争者对比率受体的亲和力，亲鼠的结合度细胞因子和骨标记水平，CCR1和CCR5表达和激活，以及巨噬细胞的归巢与AIA。给药以预防措施降低了关节炎症的严重程度。对脚踝施用MET驱动器的炎症，放射线软组织肿胀和骨侵蚀的减少。与注入盐水的对照相比，MET-RANTES显着减少了关节炎峰值的中性粒细胞和巨噬细胞的数量。外周血单核细胞中的竞争性趋化性表明，Metrantes以50％的抑制浓度分别抑制MIP-1α和MIP-1β，分别为5 nm和2 nm。此外，与对照组相比，肿瘤坏死因子A，巨噬细胞β-1β，巨噬细胞刺激因子和RANKL的水平降低。有趣的是，与对照组相比，在MET-RANTES组中，关节中CCR1和CCR5的表达和激活被下调。在功能上，MET-RANTES给药将腹膜巨噬细胞归巢降低到关节。数据表明，与Th1相关的趋化因子受体的靶向将关节炎症，骨骼破坏和细胞募集减少到与AIA关节中。
Objective. CC chemokines and their receptors play a fundamental role in trafficking and activation of leukocytes at sites of inflammation, contributing to joint damage in rheumatoid arthritis. Met-RANTES, an amino-terminal-modified methionylated form of RANTES (CCL5), antagonizes the binding of the chemokines RANTES and macrophage inflammatory protein la (MIP-1 alpha; CCL3) to their receptors CCR1 and CCR5, respectively. The aim of this study was to investigate whether Met-RANTES could ameliorate adjuvant-induced arthritis (AIA) in the rat.Methods. Using immunohistochemistry, enzymelinked immunosorbent assay, real-time reverse transcription-polymerase chain reaction, Western blot analysis, adoptive transfer, and chemotaxis, we defined joint inflammation, bony destruction, neutrophil and macrophage migration, Met-RANTES binding affinity to rat receptors, proinflammatory cytokine and bone marker levels, CCR1 and CCR5 expression and activation, and macrophage homing into joints with AIA.Results. Administration of Met-RANTES as a preventative reduced the severity of joint inflammation. Administration of Met-RANTES to ankles with AIA showed decreases in inflammation, radiographic soft tissue swelling, and bone erosion. Met-RANTES significantly reduced the number of neutrophils and macrophages at the peak of arthritis compared with saline-injected controls. Competitive chemotaxis in peripheral blood mononuclear cells demonstrated that MetRANTES inhibited MIP-1 alpha and MIP-1 beta at 50% inhibition concentrations of 5 nM and 2 nM, respectively. Furthermore, levels of tumor necrosis factor a, interleukin-1 beta, macrophage colony-stimulating factor, and RANKL were decreased in joints with AIA in the Met-RANTES group compared with the control group. Interestingly, the expression and activation of CCR1 and CCR5 in the joint were down-regulated in the Met-RANTES group compared with the control group. Functionally, Met-RANTES administration decreased adoptively transferred peritoneal macrophage homing into the joint.Conclusion. The data suggest that the targeting of Th1-associated chemokine receptors reduce joint inflammation, bone destruction, and cell recruitment into joints with AIA.