Activation of Liver X Receptor Induces Macrophage Interleukin-5 Expression
Activation of Liver X Receptor Induces Macrophage Interleukin-5 Expression
复制标题
肝脏x受体激活诱导巨噬细胞白细胞介素5表达
DOI：
10.1074/jbc.m112.403394
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发表时间：
2012-12-21
影响因子：
4.8
通讯作者：
Han, Jihong
中科院分区：
文献类型：
--
作者：
Chen, Yuanli;Duan, Yajun;Han, Jihong
IL-5 刺激 T15/EO6 IgM 抗体的产生，该抗体可以阻止巨噬细胞摄取氧化低密度脂蛋白，而巨噬细胞 IL-5 表达的缺陷会加速动脉粥样硬化的发展。肝脏X受体（LXR）是配体激活的转录因子，可以诱导巨噬细胞ABCA1表达和胆固醇外流，从而抑制动脉粥样硬化的发展。然而，尚不清楚其他机制（例如巨噬细胞 IL-5 表达的调节）是否与 LXR 的抗动脉粥样硬化特性有关。我们最初定义了巨噬细胞中的 IL-5 表达，其中 LXR 配体 (T0901317) 诱导巨噬细胞 IL-5 蛋白表达和分泌。 LXR 的过表达增加，而其敲低则抑制 IL-5 的表达。此外，我们发现 LXR 激活增加了 IL-5 转录本、启动子活性、LXR.LXR 响应元件复合物的形成以及 IL-5 蛋白稳定性。在体内，我们发现 T0901317 增加了野生型小鼠血浆中 IL-5 和总 IgM 的水平以及多个组织中 IL-5 的表达。在 LDL 受体敲除 (LDLR-/-) 小鼠中，T0901317 增加了主动脉根部区域的 IL-5 表达。综上所述，我们的研究表明巨噬细胞IL-5是LXR激活的靶基因，巨噬细胞IL-5表达的诱导可能与LXR抑制动脉粥样硬化有关。
IL-5 stimulates production of T15/EO6 IgM antibodies that can block the uptake of oxidized low density lipoprotein by macrophages, whereas a deficiency in macrophage IL-5 expression accelerates development of atherosclerosis. Liver X receptors (LXRs) are ligand-activated transcription factors that can induce macrophage ABCA1 expression and cholesterol efflux, thereby inhibiting the development of atherosclerosis. However, it remains unknown whether additional mechanisms, such as the regulation of macrophage IL-5 expression, are related to the anti-atherogenic properties of LXR. We initially defined IL-5 expression in macrophages where the LXR ligand (T0901317) induced macrophage IL-5 protein expression and secretion. The overexpression of LXR increased, whereas its knockdown inhibited IL-5 expression. Furthermore, we found that LXR activation increased IL-5 transcripts, promoter activity, formation of an LXR.LXR-responsive element complex, and IL-5 protein stability. In vivo, we found that T0901317 increased IL-5 and total IgM levels in plasma and IL-5 expression in multiple tissues in wild type mice. In LDL receptor knock-out (LDLR-/-) mice, T0901317 increased IL-5 expression in the aortic root area. Taken together, our studies demonstrate that macrophage IL-5 is a target gene for LXR activation, and the induction of macrophage IL-5 expression can be related to LXR-inhibited atherosclerosis.