Trudeau John, Hu Haizhen, Chibana Kazuyuki, Chu Hong Wei, Westcott Jay Y, Wenzel Sally E
Department of Medicine, Division of Pulmonary, National Jewish Medical and Research Center, Denver, CO 80206, USA.
J Allergy Clin Immunol. 2006 Jun;117(6):1446-54. doi: 10.1016/j.jaci.2006.01.049. Epub 2006 May 2.
Levels of COX-2 and downstream products, such as prostaglandin (PG) E2, are increased in inflammatory settings after stimulation by IL-1beta, LPS, and other innate factors. Although the TH2 cytokines IL-4 and IL-13 have been reported to decrease COX-2 levels in some cell types, neither the effect of these cytokines on other PGE2-related pathways nor their effect in primary human airway epithelial cells has been evaluated.
To determine the impact of IL-13 on PGE2 pathways in primary human airway epithelial cells.
Because PGE2 has anti-inflammatory, antifibrotic, and bronchodilating properties of relevance to asthma, the effect of IL-13 (10 ng/mL for 10 days) on PGE2 pathway elements in first-passage air-liquid interface epithelial cells from 8 endobronchial brushings (5 asthmatic subjects and 3 healthy subjects) was evaluated. mRNA and protein levels for COX-1 and COX-2, membrane-bound PGE synthase 1, 15-PG dehydrogenase, and the receptors EP2 and EP4 were quantified by means of real-time PCR and Western blotting. PGE2 levels in the supernatants were measured by means of enzyme immunoassay.
IL-13 significantly inhibited the PGE2 synthetic pathways COX-2 and PGE synthase 1 while upregulating the PGE2 metabolizing enzyme 15-PG dehydrogenase. These enzymatic changes associated and correlated with decreased supernatant PGE2 levels. Significant reductions in the mRNA for EP2 (but not EP4) were also observed. Changes in the PG pathway were both time and dose dependent (n = 3).
These data suggest that IL-13 induces systematic modulation of proteins related to the production, catabolism, and function of PGE2, which might alter inflammatory and immune responses at the level of the epithelium and the submucosa below.
Modulation of PGE2 pathways by IL-13 might alter inflammatory and repair processes in asthma.
在受到白细胞介素-1β、脂多糖及其他固有因子刺激后的炎症环境中，环氧化酶-2（COX-2）及其下游产物，如前列腺素（PG）E2的水平会升高。虽然据报道，TH2细胞因子白细胞介素-4和白细胞介素-13可降低某些细胞类型中的COX-2水平，但这些细胞因子对其他与PGE2相关途径的影响以及在原代人呼吸道上皮细胞中的作用尚未得到评估。
确定白细胞介素-13对原代人呼吸道上皮细胞中PGE2途径的影响。
鉴于PGE2具有与哮喘相关的抗炎、抗纤维化和支气管扩张特性，评估了白细胞介素-13（10 ng/mL，持续10天）对来自8份支气管刷检样本（5名哮喘患者和3名健康受试者）的第一代气液界面上皮细胞中PGE2途径元件的影响。通过实时聚合酶链反应和蛋白质印迹法对COX-1和COX-2、膜结合型PGE合酶1、15-PG脱氢酶以及受体EP2和EP4的信使核糖核酸和蛋白质水平进行定量分析。通过酶免疫测定法测量上清液中的PGE2水平。
白细胞介素-13显著抑制PGE2合成途径中的COX-2和PGE合酶1，同时上调PGE2代谢酶15-PG脱氢酶。这些酶促变化与上清液中PGE2水平降低相关且具有相关性。还观察到EP2（而非EP4）的信使核糖核酸显著减少。PG途径的变化具有时间和剂量依赖性（n = 3）。
这些数据表明，白细胞介素-13可诱导对与PGE2产生、分解代谢和功能相关蛋白质的系统性调节，这可能会改变上皮层及下方黏膜下层的炎症和免疫反应。
白细胞介素-13对PGE2途径的调节可能会改变哮喘中的炎症和修复过程。
