From the Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (M.R., K.G., C.N.V., A.B.H., F.K., S.E.K., M.V.A.).
Department of Biomedical Sciences, University of Missouri, Columbia (L.A.G.).
Arterioscler Thromb Vasc Biol. 2018 Jun;38(6):1297-1308. doi: 10.1161/ATVBAHA.118.310929. Epub 2018 Apr 19.
To test the hypothesis that loss of IL-19 (interleukin-19) exacerbates atherosclerosis. APPROACH AND RESULTS: mice were crossed into (low-density lipoprotein receptor knock out) mice. Double knockout (dKO) mice had increased plaque burden in aortic arch and root compared with controls after 14 weeks of high-fat diet (HFD). dKO mice injected with 10 ng/g per day rmIL-19 had significantly less plaque compared with controls. qRT-PCR and Western blot analysis revealed dKO mice had increased systemic and intraplaque polarization of T cells and macrophages to proinflammatory T1 and M1 phenotypes, and also significantly increased TNF (tumor necrosis factor)-α expression in spleen and aortic arch compared with controls. Bone marrow transplantation suggests that immune cells participate in IL-19 protection. Bone marrow-derived macrophages and vascular smooth muscle cells isolated from dKO mice had a significantly greater expression of inflammatory cytokine mRNA and protein compared with controls. Spleen and aortic arch from dKO mice had significantly increased expression of the mRNA stability protein HuR (human antigen R). Bone marrow-derived macrophage and vascular smooth muscle cell isolated from dKO mice also had greater HuR abundance. HuR stabilizes proinflammatory transcripts by binding AU-rich elements in the 3' untranslated region. Cytokine and HuR mRNA stability were increased in dKO bone marrow-derived macrophage and vascular smooth muscle cell, which was rescued by addition of IL-19 to these cells. IL-19-induced expression of miR133a, which targets and reduced HuR abundance; miR133a levels were lower in dKO mice compared with controls.
These data indicate that IL-19 is an atheroprotective cytokine which decreases the abundance of HuR, leading to reduced inflammatory mRNA stability.
验证白细胞介素-19（IL-19）缺失会加重动脉粥样硬化的假说。
将 小鼠与（低密度脂蛋白受体敲除）小鼠杂交。与对照组相比，经过 14 周高脂肪饮食（HFD）后，双敲除（dKO）小鼠的主动脉弓和根部斑块负担增加。每天向 dKO 小鼠注射 10ng/g 的 rmIL-19 后，与对照组相比，斑块明显减少。qRT-PCR 和 Western blot 分析显示，dKO 小鼠体内和斑块内 T 细胞和巨噬细胞向促炎 T1 和 M1 表型极化增加，与对照组相比，脾脏和主动脉弓中的 TNF（肿瘤坏死因子）-α 表达也显著增加。骨髓移植表明免疫细胞参与了 IL-19 的保护作用。与对照组相比，dKO 小鼠骨髓来源的巨噬细胞和血管平滑肌细胞的炎症细胞因子 mRNA 和蛋白表达显著增加。与对照组相比，dKO 小鼠的脾脏和主动脉弓中 HuR（人类抗原 R）的 mRNA 表达显著增加。从 dKO 小鼠分离的骨髓来源的巨噬细胞和血管平滑肌细胞也具有更高的 HuR 丰度。HuR 通过结合 3'非翻译区中的 AU 富含元件稳定促炎转录本。dKO 骨髓来源的巨噬细胞和血管平滑肌细胞中的细胞因子和 HuR mRNA 稳定性增加，通过向这些细胞添加 IL-19 可以挽救这种情况。IL-19 诱导 miR133a 的表达，miR133a 靶向并降低 HuR 的丰度；与对照组相比，dKO 小鼠中的 miR133a 水平较低。
这些数据表明，IL-19 是一种抗动脉粥样硬化细胞因子，可降低 HuR 的丰度，从而降低炎症 mRNA 的稳定性。
