Jiang Haihong, Xie Yan, Abel Peter W, Wolff Dennis W, Toews Myron L, Panettieri Reynold A, Casale Thomas B, Tu Yaping
1 Department of Pharmacology, Creighton University School of Medicine, Omaha, Nebraska.
2 Department of Biomedical Sciences, University of South Carolina School of Medicine at Greenville, Greenville, South Carolina.
Am J Respir Cell Mol Biol. 2015 Jul;53(1):42-9. doi: 10.1165/rcmb.2014-0319OC.
G protein-coupled receptors (GPCRs) are important regulators of cell functions in asthma. We recently reported that regulator of G-protein signaling (RGS) 2, a selective modulator of Gq-coupled GPCRs, is a key regulator of airway hyper-responsiveness (AHR), the pathophysiologic hallmark of asthma. Because RGS2 protein levels in airway cells were significantly lower in patients with asthma compared with patients without asthma, we further investigated the potential pathological importance of RGS2 repression in asthma. The human RGS2 gene maps to chromosome 1q31. We first screened patients with asthma for RGS2 gene promoter single-nucleotide polymorphisms (SNPs) and found significant differences in the distribution of two RGS2 SNPs (A638G, rs2746071 and C395G, rs2746072) between patients with asthma and nonasthmatic subjects. These two SNPs are always associated with each other and have the same higher prevalence in patients with asthma (65%) as compared with nonasthmatic subjects (35%). Point mutations corresponding to these SNPs decrease RGS2 promoter activity by 44%. The importance of RGS2 down-regulation was then determined in an acute IL-13 mouse model of asthma. Intranasal administration of IL-13 in mice also decreased RGS2 expression in lungs by ∼50% and caused AHR. Although naive RGS2 knockout (KO) mice exhibit spontaneous AHR, acute IL-13 exposure further increased AHR in RGS2 KO mice. Loss of RGS2 also significantly enhanced IL-13-induced mouse airway remodeling, including peribronchial smooth muscle thickening and fibrosis, without effects on goblet cell hyperplasia or airway inflammation in mice. Thus, genetic variations and increased inflammatory cytokines can lead to RGS2 repression, which exacerbates AHR and airway remodeling in asthma.
G蛋白偶联受体（GPCRs）是哮喘中细胞功能的重要调节因子。我们最近报道，作为Gq偶联GPCRs的选择性调节剂，G蛋白信号调节因子（RGS）2是气道高反应性（AHR）的关键调节因子，而气道高反应性是哮喘的病理生理标志。由于与无哮喘患者相比，哮喘患者气道细胞中的RGS2蛋白水平显著降低，我们进一步研究了RGS2抑制在哮喘中的潜在病理重要性。人类RGS2基因定位于染色体1q31。我们首先对哮喘患者进行RGS2基因启动子单核苷酸多态性（SNP）筛查，发现哮喘患者与非哮喘受试者之间存在两种RGS2 SNP（A638G，rs2746071和C395G，rs2746072）分布的显著差异。这两种SNP总是相互关联，与非哮喘受试者（35%）相比，在哮喘患者中具有相同的较高患病率（65%）。与这些SNP对应的点突变使RGS2启动子活性降低44%。然后在哮喘急性IL-13小鼠模型中确定RGS2下调的重要性。小鼠鼻内给予IL-13也使肺中RGS2表达降低约50%并引起气道高反应性。虽然未处理的RGS2基因敲除（KO）小鼠表现出自发性气道高反应性，但急性IL-13暴露进一步增加了RGS2 KO小鼠的气道高反应性。RGS2的缺失还显著增强了IL-13诱导的小鼠气道重塑，包括支气管周围平滑肌增厚和纤维化，但对小鼠杯状细胞增生或气道炎症无影响。因此，基因变异和炎性细胞因子增加可导致RGS2抑制，从而加剧哮喘中的气道高反应性和气道重塑。
