Attenuation of experimental atherosclerosis by interleukin-19.
Attenuation of experimental atherosclerosis by interleukin-19.
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DOI：
10.1161/atvbaha.113.301521
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发表时间：
2013-10
期刊：
影响因子：
--
通讯作者：
Autieri MV
中科院分区：
文献类型：
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作者：
Ellison S;Gabunia K;Kelemen SE;England RN;Scalia R;Richards JM;Orr AW;Traylor JG Jr;Rogers T;Cornwell W;Berglund LM;Goncalves I;Gomez MF;Autieri MV
白细胞介素-19（IL-19）是公认的Th 2类抗炎白细胞介素。其在动脉粥样硬化形成中的表达和潜在作用尚不清楚。IL-19在正常动脉中未检测到，并且在来自有症状患者与无症状患者的斑块中更大程度地表达，表明补偿-反调节功能。我们测试了IL-19是否可以减少易感小鼠的动脉粥样硬化，并确定了合理的机制。与对照组相比，喂食致动脉粥样硬化饮食并注射1.0ng/g/天或10.0ng/g/天rmIL-19的LDLR−/−小鼠主动脉弓中的斑块面积显著减少（p<0.0001）。体重增加，胆固醇和甘油三酯水平没有显着差异。IL-19处理的小鼠脾细胞中的基因表达显示免疫细胞Th 2极化，T-bet、IFNγ、IL-1β和IL-12β的表达降低，而GATA 3和FoxP 3 mRNA的表达增加。在IL-19处理的小鼠中，更大百分比的淋巴细胞是Th 2极化的。通过免疫组织化学对斑块的细胞表征表明，与对照相比，IL-19处理的小鼠具有显著更少的巨噬细胞浸润（p<0.001）。活体显微镜检查显示，与对照组相比，注射IL-19并喂食致动脉粥样硬化饮食的野生型小鼠的白细胞粘附显著减少。用IL-19处理培养的内皮细胞（EC）、血管平滑肌细胞（VSMC）和骨髓源性巨噬细胞（BMDM）导致趋化因子mRNA和mRNA稳定性蛋白HuR显著降低。这些数据表明IL-19是实验性动脉粥样硬化的有效抑制剂，具有多种机制，包括免疫细胞极化、巨噬细胞粘附减少和基因表达减少。这可能将IL-19确定为限制血管炎症的新型治疗剂。
Interleukin-19 (IL-19) is putative Th2, anti-inflammatory interleukin. Its expression in, and potential role in atherogenesis is unknown. IL-19 is not detected in normal artery, and is expressed to a greater degree in plaque from symptomatic vs. asymptomatic patients, suggesting a compensatory-counter regulatory function. We tested if IL-19 could reduce atherosclerosis in susceptible mice, and identified plausible mechanisms. LDLR−/− mice fed an atherogenic diet and injected with either 1.0ng/g/day or 10.0ng/g/day rmIL-19 had significantly less plaque area in the aortic arch compared with controls (p<0.0001). Weight gain, cholesterol and triglyceride levels were not significantly different. Gene expression in splenocytes from IL-19 treated mice demonstrated immune cell Th2 polarization, with decreased expression of T-bet, IFNγ, IL-1β and IL-12β, and increased expression of GATA3 and FoxP3 mRNA. A greater percentage of lymphocytes were Th2 polarized in IL-19 treated mice. Cellular characterization of plaque by immunohistochemistry demonstrated IL-19 treated mice have significantly less macrophage infiltrate compared with controls (p<0.001). Intravital microscopy revealed significantly less leukocyte adhesion in wild-type mice injected with IL-19 and fed an atherogenic diet compared with controls. Treatment of cultured endothelial cells (EC), vascular smooth muscle cells (VSMC), and bone marrow-derived macrophages (BMDM) with IL-19 resulted in a significant decrease in chemokine mRNA, and in the mRNA-stability protein HuR. These data suggest IL-19 is a potent inhibitor of experimental atherosclerosis, with diverse mechanisms including immune cell polarization, decrease in macrophage adhesion, and decrease in gene expression. This may identify IL-19 as a novel therapeutic to limit vascular inflammation.