In vivo inhibition of angiogenesis by interleukin-13 gene therapy in a rat model of rheumatoid arthritis
In vivo inhibition of angiogenesis by interleukin-13 gene therapy in a rat model of rheumatoid arthritis
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DOI：
10.1002/art.22823
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发表时间：
2007-08-01
影响因子：
--
通讯作者：
Koch, Alisa E.
中科院分区：
文献类型：
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作者：
Haas, Christian S.;Amin, M. Asif;Koch, Alisa E.
目标。白细胞介素-13 （IL-13）是一种影响血管形成的多效细胞因子，是类风湿性关节炎（RA）滑膜组织的重要组成部分。本研究采用基因治疗方法，采用佐剂诱导的ra大鼠关节炎模型，探讨IL-13在血管生成中的作用。雌性大鼠踝关节预防性注射含人IL-13 （AxCAIL-13）的腺病毒载体、无插入物的对照载体（AxCANI）或磷酸盐缓冲盐水（PBS）。在关节炎高峰期采集关节，评估组织学和生化特征。axcail -13处理后的关节匀浆血红蛋白水平较低，表明关节血管性降低，内皮细胞迁移和小管形成均明显受到抑制（P < 0.05）。同样，AxCAIL-13在大鼠主动脉环实验中抑制毛细血管发芽，在Matrigel塞体内实验中抑制血管生长。IL-13基因传递导致磷酸化的ERK-1/2和蛋白激酶Ca/ β II的上调和关联，提示IL-13介导的血管停滞的新途径。AxCAIL-13的血管抑制作用与下调促血管生成细胞因子（IL-18、细胞因子诱导的中性粒细胞趋化因子I/CXCL1、脂多糖诱导的CXC趋化因子/CXCL5）和上调血管生成抑制剂内皮抑素有关。与AxCANI和PBS处理相比，IL-13作用下参与血管生成的基质金属蛋白酶2和9的表达和活性受到抑制。我们的研究结果支持IL-13作为体内抗血管生成因子的作用，并为其在RA中用于控制病理性新生血管提供了理论依据。
Objective. Interleukin-13 (IL-13) is a pleiotropic cytokine that can affect vessel formation, an important component of the rheumatoid arthritis (RA) synovial tissue pannus. The purpose of this study was to use a gene therapy approach to investigate the role of IL-13 in angiogenesis in vivo, using a rat adjuvant-induced arthritis model of RA.Methods. Ankle joints of female rats were injected preventatively with an adenovirus vector containing human IL-13 (AxCAIL-13), a control vector with no insert (AxCANI), or phosphate buffered saline (PBS). Joints were harvested at the peak of arthritis, and histologic and biochemical features were evaluated.Results. AxCAIL-13-treated joint homogenates had lower hemoglobin levels, suggesting reduced joint vascularity, and both endothelial cell migration and tube formation were significantly inhibited (P < 0.05). Similarly, AxCAIL-13 inhibited capillary sprouting in the rat aortic ring assay and vessel growth in the Matrigel plug in vivo assay. IL-13 gene delivery resulted in up-regulation and association of phosphorylated ERK-1/2 and protein kinase Ca/beta II, suggesting a novel pathway in IL-13-mediated angiostasis. The angiostatic effect of AxCAIL-13 was associated with downregulation of proangiogenic cytokines (IL-18, cytokine-induced neutrophil chemoattractant I/CXCL1, lipopolysaccharide-induced CXC chemokine/CXCL5) and up-regulation of the angiogenesis inhibitor endostatin. The expression and activity of matrix metalloproteinases 2 and 9, which participate in angiogenesis, was impaired in response to IL-13 as compared with AxCANI and PBS treatment.Conclusion. Our findings support a role for IL-13 as an in vivo antiangiogenic factor and provide a rationale for its use in RA to control pathologic neovascularization.