title: Regulator of G-protein signaling 2 repression exacerbates airway hyper-responsiveness and remodeling in asthma.
abstract: 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.
authors.affiliation: 1 Department of Pharmacology, Creighton University School of Medicine, Omaha, Nebraska.
authors.forename: Haihong
authors.initials: H
authors.lastname: Jiang
authors.affiliation: 1 Department of Pharmacology, Creighton University School of Medicine, Omaha, Nebraska.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xie
authors.affiliation: 1 Department of Pharmacology, Creighton University School of Medicine, Omaha, Nebraska.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Abel
authors.affiliation: 2 Department of Biomedical Sciences, University of South Carolina School of Medicine at Greenville, Greenville, South Carolina.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Wolff
authors.affiliation: 3 Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Myron L
authors.initials: ML
authors.lastname: Toews
authors.affiliation: 4 Pulmonary, Allergy and Critical Care Division, Airways Biology Initiative, University of Pennsylvania, Philadelphia, Pennsylvania; and.
authors.forename: Reynold A
authors.initials: RA
authors.lastname: Panettieri
authors.affiliation: 5 Department of Internal Medicine, University of South Florida School of Medicine, Tampa, Florida.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Casale
authors.affiliation: 1 Department of Pharmacology, Creighton University School of Medicine, Omaha, Nebraska.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Tu
mesh_terms: D056151:Airway Remodeling; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D018793:Interleukin-13 / Q000633:toxicity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018793:Interleukin-13; D020710:RGS Proteins; C087182:RGS2 protein, human; C105345:Rgs2 protein, mouse
keywords: RGS2; airway hyper-responsiveness; airway remodeling; asthma; polymorphisms