维生素 D 在激素抵抗和激素敏感哮喘患者单核细胞中的抗炎和增强皮质类固醇作用。
Anti-inflammatory and corticosteroid-enhancing actions of vitamin D in monocytes of patients with steroid-resistant and those with steroid-sensitive asthma.
机构信息
Department of Pediatrics, National Jewish Health, Denver, Colo.
Department of Pediatrics, National Jewish Health, Denver, Colo; Department of Pediatrics, University of Colorado Denver, Aurora, Colo.
出版信息
J Allergy Clin Immunol. 2014 Jun;133(6):1744-52.e1. doi: 10.1016/j.jaci.2013.12.004. Epub 2014 Jan 11.
BACKGROUND
Vitamin D is known for its anti-inflammatory effects.
OBJECTIVE
Vitamin D regulation of responses in patients with steroid-resistant (SR) versus steroid-sensitive (SS) asthma has not been studied.
METHODS
Peripheral blood cells from 11 patients with SR asthma and 8 patients with SS asthma were preincubated with 1,25-dihydroxyvitamin D (1,25[OH]2D [VitD]), followed by dexamethasone (DEX) treatment and LPS stimulation. LPS-induced phosphorylated p38 mitogen-activated protein kinase (p-p38) in monocytes was examined by means of flow cytometry. Mitogen-activated protein kinase phosphatase-1 (MKP-1) mRNA expression, which inhibits p-p38, was analyzed by means of real-time PCR. Glucocorticoid receptor (GR) binding and histone H4 acetylation in the glucocorticoid response element of the MKP-1 promoter in monocytes were analyzed by means of chromatin immunoprecipitation.
RESULTS
DEX significantly inhibited LPS-induced p-p38 in monocytes from patients with SS asthma but not those from patients with SR asthma (P < .01). VitD inhibited LPS-induced p-p38 in monocytes from both patient groups (P < .01) but enhanced DEX suppression of LPS-induced p-p38 only in monocytes from patients with SS asthma (P < .01). VitD induced MKP-1 expression and enhanced DEX induction of MKP-1 in both patients with SS asthma and patients with SR asthma. VitD/DEX-induced MKP-1 mRNA levels remained significantly lower in monocytes from patients with SR asthma (P < .05). DEX-stimulated recruitment of GR and histone H4 acetylation at the glucocorticoid response element 4.6 kbp upstream of the MKP-1 gene were significantly lower in monocytes from patients with SR asthma compared with those from patients with SS asthma. VitD pretreatment enhanced DEX-induced GR binding and histone acetylation in monocytes from both patient groups. However, GR binding and histone H4 acetylation remained significantly lower in monocytes from patients with SR asthma.
CONCLUSION
VitD demonstrated anti-inflammatory and corticosteroid-enhancing effects in monocytes of patients with SR asthma and patients with SS asthma. However, the responses to corticosteroids in patients with SR asthma remained significantly lower than those in patients with SS asthma.
背景
维生素 D 以其抗炎作用而闻名。
目的
尚未研究维生素 D 对类固醇耐药（SR）与类固醇敏感（SS）哮喘患者反应的调节作用。
方法
用 1,25-二羟维生素 D（1,25[OH]2D[VitD]）预孵育 11 例 SR 哮喘患者和 8 例 SS 哮喘患者的外周血单个核细胞，然后用地塞米松（DEX）处理和 LPS 刺激。通过流式细胞术检测单核细胞中 LPS 诱导的磷酸化 p38 丝裂原活化蛋白激酶（p-p38）。通过实时 PCR 分析抑制 p-p38 的丝裂原激活蛋白激酶磷酸酶-1（MKP-1）mRNA 表达。通过染色质免疫沉淀分析单核细胞中 MKP-1 启动子糖皮质激素反应元件中的糖皮质激素受体（GR）结合和组蛋白 H4 乙酰化。
结果
DEX 显著抑制 SS 哮喘患者单核细胞中 LPS 诱导的 p-p38，但不抑制 SR 哮喘患者单核细胞中 LPS 诱导的 p-p38（P<0.01）。VitD 抑制两组患者单核细胞中 LPS 诱导的 p-p38（P<0.01），但仅增强 SS 哮喘患者单核细胞中 DEX 对 LPS 诱导的 p-p38 的抑制（P<0.01）。VitD 诱导 SS 哮喘和 SR 哮喘患者的 MKP-1 表达，并增强 DEX 诱导的 MKP-1。SR 哮喘患者单核细胞中 VitD/DEX 诱导的 MKP-1 mRNA 水平仍显著低于 SS 哮喘患者（P<0.05）。DEX 刺激的 GR 募集和 MKP-1 基因上游 4.6 kbp 处糖皮质激素反应元件的组蛋白 H4 乙酰化在 SR 哮喘患者单核细胞中明显低于 SS 哮喘患者。VitD 预处理增强了两组患者单核细胞中 DEX 诱导的 GR 结合和组蛋白乙酰化。然而，SR 哮喘患者单核细胞中 GR 结合和组蛋白 H4 乙酰化仍明显低于 SS 哮喘患者。
结论
VitD 在 SR 哮喘和 SS 哮喘患者的单核细胞中表现出抗炎和皮质类固醇增强作用。然而，SR 哮喘患者对皮质类固醇的反应仍明显低于 SS 哮喘患者。
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