Interleukin-37 suppresses the inflammatory response to protect cardiac function in old endotoxemic mice.
Interleukin-37 suppresses the inflammatory response to protect cardiac function in old endotoxemic mice.
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DOI：
10.1016/j.cyto.2017.02.008
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发表时间：
2017-07
期刊：
影响因子：
3.8
通讯作者：
Meng X
中科院分区：
文献类型：
--
作者：
Li J;Zhai Y;Ao L;Hui H;Fullerton DA;Dinarello CA;Meng X
老年小鼠内毒素血症引起的心肌炎症反应增强，导致心功能不全加重。抗炎细胞因子白细胞介素（IL）-37对先天免疫应答具有广泛的影响。我们假设IL-37抑制心肌炎症反应，以保护老年小鼠内毒素血症期间的心功能。用脂多糖（LPS，0.5 mg/kg，iv）或生理盐水（0.1 ml/小鼠，iv）处理老年（20-24个月）野生型（WT）和IL-37转基因（IL-37 tg）小鼠。6小时后，使用压力-容积微导管评估左心室（LV）功能。检测血浆和心肌组织中单核细胞趋化蛋白-1（MCP-1）、肿瘤坏死因子-α（TNF-α）、白细胞介素（IL）-1β和IL-6水平，以及心肌组织中单核细胞密度。用LPS（0.2 μg/ml）处理从WT和IL-37 tg小鼠分离的心脏微血管内皮细胞0.5-24小时。免疫印迹法检测细胞核因子-κ B（NF-κB）p65磷酸化水平，酶联免疫吸附法检测细胞培养上清液中MCP-1水平。老年WT内毒素血症小鼠的LV功能障碍伴随MCP-1上调、单核细胞心肌蓄积以及TNF-α、IL-1β和IL-6的产生。IL-37的表达抑制了老年小鼠对内毒素血症的心肌炎症反应，从而改善了LV功能。用重组IL-37治疗老年WT内毒素血症小鼠也改善了LV功能。体外实验显示，IL-37 tg小鼠的心脏微血管内皮细胞在LPS刺激后具有减弱的NF-κB活化和MCP-1产生。总之，IL-37是有效的，以抑制心肌炎症，并防止心脏功能障碍，在老年小鼠内毒素血症。
Myocardial inflammatory responses to endotoxemia are enhanced in old mice, which results in worse cardiac dysfunction. Anti-inflammatory cytokine interleukin (IL)-37 has a broad effect on innate immunoresponses. We hypothesized that IL-37 suppresses myocardial inflammatory responses to protect cardiac function during endotoxemia in old mice. Old (20–24 month) wild-type (WT), and IL-37 transgenic (IL-37tg) mice were treated with lipopolysaccharide (LPS, 0.5 mg/kg, iv) or normal saline (0.1 ml/mouse, iv). Six hours later, left ventricle (LV) function was assessed using a pressure-volume microcatheter. Levels of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 in plasma and myocardial tissue, as well as mononuclear cell density in the myocardium, were examined. Cardiac microvascular endothelial cells isolated from WT and IL-37tg mice were treated with LPS (0.2 μg/ml) for 0.5–24 hours. Nuclear factor-kappa B (NF-κB) p65 phosphorylation was examined by immunoblotting, and MCP-1 levels in cell culture supernatant was determined using enzyme-linked immunosorbent assay. LV dysfunction in old WT endotoxemic mice was accompanied by up-regulated MCP-1, myocardial accumulation of mononuclear cells and production of TNF-α, IL-1β and IL-6. Expression of IL-37 suppressed myocardial inflammatory responses to endotoxemia in old mice, resulting in improved LV function. Treatment of old WT endotoxemic mice with recombinant IL-37 also improved LV function. In vitro experiments revealed that cardiac microvascular endothelial cells from IL-37tg mice had attenuated NF-κB activation and MCP-1 production following LPS stimulation. In conclusion, IL-37 is potent to suppress myocardial inflammation and protects against cardiac dysfunction during endotoxemia in old mice.