PDF(Pubmed)
Abstract：
OBJECTIVE: To assess the role of the interleukin (IL)-17 A/IL-17 receptor A (IL-17RA) in Kawasaki disease (KD)-related coronary arteritis (CA).
METHODS: In human study, the plasma levels of IL-17 A and coronary arteries were concurrently examined in acute KD patients. In vitro responses of human coronary endothelial cells to plasma stimulation were investigated with and without IL-17RA neutralization. A murine model of Lactobacillus casei cell-wall extract (LCWE)-induced CA using wild-type Balb/c and Il17ra-deficient mice were also inspected.
RESULTS: The plasma levels of IL-17 A were significantly higher in KD patients before intravenous immunoglobulin therapy, especially in those with coronary artery lesion. The pre-IVIG IL-17 A levels positively correlated with maximal z scores of coronary diameters and plasma-induced endothelial mRNA levels of chemokine (C-X-C motif) ligand-1, IL-8, and IL-17RA. IL-17RA blockade significantly reduced such endothelial upregulations of aforementioned three genes and inducible nitric oxide synthase, and neutrophil transmigration. IL-17RA expression was enhanced on peripheral blood mononuclear cells in pre-IVIG KD patients, and in the aortic rings and spleens of the LCWE-stimulated mice. LCWE-induced CA composed of dual-positive Ly6G- and IL-17 A-stained infiltrates. Il17ra-deficient mice showed reduced CA severity with the fewer number of neutrophils and lower early inducible nitric oxide synthase and chemokine (C-X-C motif) ligand-1 mRNA expressions than Il17ra+/+ littermates, and absent IL-17RA upregulation at aortic roots.
CONCLUSIONS: IL-17 A/IL-17RA axis may play a role in mediating aortic neutrophil chemoattraction, thus contributory to the severity of CA in both humans and mice. These findings may help to develop a new therapeutic strategy toward ameliorating KD-related CA.
METHODS: In human study, the plasma levels of IL-17 A and coronary arteries were concurrently examined in acute KD patients. In vitro responses of human coronary endothelial cells to plasma stimulation were investigated with and without IL-17RA neutralization. A murine model of Lactobacillus casei cell-wall extract (LCWE)-induced CA using wild-type Balb/c and Il17ra-deficient mice were also inspected.
RESULTS: The plasma levels of IL-17 A were significantly higher in KD patients before intravenous immunoglobulin therapy, especially in those with coronary artery lesion. The pre-IVIG IL-17 A levels positively correlated with maximal z scores of coronary diameters and plasma-induced endothelial mRNA levels of chemokine (C-X-C motif) ligand-1, IL-8, and IL-17RA. IL-17RA blockade significantly reduced such endothelial upregulations of aforementioned three genes and inducible nitric oxide synthase, and neutrophil transmigration. IL-17RA expression was enhanced on peripheral blood mononuclear cells in pre-IVIG KD patients, and in the aortic rings and spleens of the LCWE-stimulated mice. LCWE-induced CA composed of dual-positive Ly6G- and IL-17 A-stained infiltrates. Il17ra-deficient mice showed reduced CA severity with the fewer number of neutrophils and lower early inducible nitric oxide synthase and chemokine (C-X-C motif) ligand-1 mRNA expressions than Il17ra+/+ littermates, and absent IL-17RA upregulation at aortic roots.
CONCLUSIONS: IL-17 A/IL-17RA axis may play a role in mediating aortic neutrophil chemoattraction, thus contributory to the severity of CA in both humans and mice. These findings may help to develop a new therapeutic strategy toward ameliorating KD-related CA.
摘要：
目的：评估白细胞介素（IL）-17A/IL-17受体A（IL-17RA）在川崎病（KD）相关性冠状动脉炎（CA）中的作用。
方法：在人体研究中，同时检测急性KD患者血浆IL-17A和冠状动脉水平。在有和没有IL-17RA中和的情况下，研究了人冠状动脉内皮细胞对血浆刺激的体外反应。还检查了使用野生型Balb/c和Il17ra缺陷小鼠的干酪乳杆菌细胞壁提取物（LCWE）诱导的CA的鼠模型。
结果：静脉注射免疫球蛋白治疗前，KD患者的血浆IL-17A水平明显升高，尤其是冠状动脉病变的患者。前IVIGIL-17A水平与冠状动脉直径的最大z评分和血浆诱导的趋化因子（C-X-C基序）配体-1，IL-8和IL-17RA的内皮mRNA水平呈正相关。IL-17RA阻断显著降低上述三种基因和诱导型一氧化氮合酶的内皮上调,和中性粒细胞迁移。IL-17RA在前IVIGKD患者外周血单个核细胞上的表达增强,以及LCWE刺激小鼠的主动脉环和脾脏。LCWE诱导的CA由双重阳性Ly6G-和IL-17A-染色的浸润物组成。Il17ra缺陷小鼠的CA严重程度降低，中性粒细胞数量减少，早期诱导型一氧化氮合酶和趋化因子（C-X-C基序）配体-1mRNA表达低于Il17ra/同窝同窝，并且在主动脉根部没有IL-17RA上调。
结论：IL-17A/IL-17RA轴可能在介导主动脉中性粒细胞化学吸引中起作用，因此有助于CA在人类和小鼠的严重程度。这些发现可能有助于开发一种新的治疗策略来改善KD相关的CA。
方法：在人体研究中，同时检测急性KD患者血浆IL-17A和冠状动脉水平。在有和没有IL-17RA中和的情况下，研究了人冠状动脉内皮细胞对血浆刺激的体外反应。还检查了使用野生型Balb/c和Il17ra缺陷小鼠的干酪乳杆菌细胞壁提取物（LCWE）诱导的CA的鼠模型。
结果：静脉注射免疫球蛋白治疗前，KD患者的血浆IL-17A水平明显升高，尤其是冠状动脉病变的患者。前IVIGIL-17A水平与冠状动脉直径的最大z评分和血浆诱导的趋化因子（C-X-C基序）配体-1，IL-8和IL-17RA的内皮mRNA水平呈正相关。IL-17RA阻断显著降低上述三种基因和诱导型一氧化氮合酶的内皮上调,和中性粒细胞迁移。IL-17RA在前IVIGKD患者外周血单个核细胞上的表达增强,以及LCWE刺激小鼠的主动脉环和脾脏。LCWE诱导的CA由双重阳性Ly6G-和IL-17A-染色的浸润物组成。Il17ra缺陷小鼠的CA严重程度降低，中性粒细胞数量减少，早期诱导型一氧化氮合酶和趋化因子（C-X-C基序）配体-1mRNA表达低于Il17ra/同窝同窝，并且在主动脉根部没有IL-17RA上调。
结论：IL-17A/IL-17RA轴可能在介导主动脉中性粒细胞化学吸引中起作用，因此有助于CA在人类和小鼠的严重程度。这些发现可能有助于开发一种新的治疗策略来改善KD相关的CA。
