IL-35 (Interleukin-35) Suppresses Endothelial Cell Activation by Inhibiting Mitochondrial Reactive Oxygen Species-Mediated Site-Specific Acetylation of H3K14 (Histone 3 Lysine 14).
IL-35 (Interleukin-35) Suppresses Endothelial Cell Activation by Inhibiting Mitochondrial Reactive Oxygen Species-Mediated Site-Specific Acetylation of H3K14 (Histone 3 Lysine 14).
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DOI：
10.1161/atvbaha.117.310626
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Yang X
中科院分区：
文献类型：
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作者：
Li X;Shao Y;Sha X;Fang P;Kuo YM;Andrews AJ;Li Y;Yang WY;Maddaloni M;Pascual DW;Luo JJ;Jiang X;Wang H;Yang X
IL-35是一种抗炎细胞因子，其通过诱导调节性T细胞和调节性B细胞以及抑制效应T细胞和巨噬细胞来抑制免疫应答。致动脉粥样硬化刺激是否诱导IL-35，以及IL-35是否抑制致动脉粥样硬化脂质诱导的内皮细胞（EC）活化和动脉粥样硬化仍然是未知的。高脂血症刺激（包括溶血磷脂酰胆碱（LPC））诱导的EC激活被认为是单核细胞募集和动脉粥样硬化的起始步骤。在这项研究中，我们研究了IL-35在早期动脉粥样硬化中的表达，以及IL-35在抑制LPC诱导的EC激活中的作用和机制。利用微阵列和ELISA，我们发现IL-35及其受体在载脂蛋白E（ApoE）基因敲除小鼠，动脉粥样硬化小鼠模型，以及在高胆固醇血症患者的血浆中的动脉粥样硬化早期显著诱导。此外，我们发现IL-35抑制LPC诱导的单核细胞粘附到人主动脉内皮细胞（HAEC）。此外，我们的RNA-Seq分析表明，IL-35选择性抑制LPC诱导的EC激活相关基因，如ICAM-1。从机制上讲，使用流式细胞术、质谱、电子自旋共振分析和CHIP-Seq分析，我们发现IL-35阻断LPC诱导的线粒体活性氧（mtROS），这是诱导位点特异性组蛋白3赖氨酸14（H3 K14）乙酰化所必需的，增加了ICAM-1启动子中促炎转录因子AP-1的结合，和诱导HAEC中ICAM-1的转录。最后，IL-35细胞因子疗法抑制ApoE敲除小鼠中动脉粥样硬化病变的发展。IL-35在动脉粥样硬化发展过程中被诱导并抑制mtROS-H3 K14 ac-AP-1介导的EC活化。
IL-35 is an anti-inflammatory cytokine, which inhibits immune responses by inducing regulatory T cells and regulatory B cells, and suppressing effector T cells and macrophages. It remains unknown whether atherogenic stimuli induce IL-35, and whether IL-35 inhibits atherogenic lipid-induced endothelia cell (EC) activation and atherosclerosis. EC activation induced by hyperlipidemia stimuli including lysophosphatidylcholine (LPC) is considered as an initiation step for monocyte recruitment and atherosclerosis. In this study, we examined the expression of IL-35 during early atherosclerosis, and the roles and mechanisms of IL-35 in suppressing LPC-induced EC activation. Using microarray and ELISA, we found that IL-35 and its receptor are significantly induced during early atherosclerosis in the aortas and plasma of apolipoprotein E (ApoE) knockout mice, an atherosclerotic mouse model, as well as in the plasma of hypercholesterolemic patients. In addition, we found that IL-35 suppresses LPC-induced monocyte adhesion to human aortic ECs (HAEC). Furthermore, our RNA-Seq analysis shows that IL-35 selectively inhibits LPC-induced EC activation-related genes such as ICAM-1. Mechanistically, using flow cytometry, mass spectrometry, electron spin resonance analyses, and CHIP-Seq analyses, we found that IL-35 blocks LPC-induced mitochondrial reactive oxygen species (mtROS), which are required for the induction of site-specific histone 3 lysine 14 (H3K14) acetylation, increased binding of pro-inflammatory transcription factor AP-1 in the promoter of ICAM-1, and induction of ICAM-1 transcription in HAEC. Finally, IL-35 cytokine therapy suppresses atherosclerotic lesion development in ApoE knockout mice. IL-35 is induced during atherosclerosis development and inhibits mtROS-H3K14ac-AP-1-mediated EC activation.