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Immunology - Molecular Biology - Physiology - Respiratory Medicine

G Protein ß?-Subunit Signaling Mediates Airway Hyperresponsiveness and Inflammation in Allergic Asthma
Published: Wednesday, February 22, 2012
Author: Gustavo Nino et al.

by Gustavo Nino, Aihua Hu, Judith S. Grunstein, Joseph McDonough, Portia A. Kreiger, Maureen B. Josephson, John K. Choi, Michael M. Grunstein

Since the Gß? subunit of Gi protein has been importantly implicated in regulating immune and inflammatory responses, this study investigated the potential role and mechanism of action of Gß? signaling in regulating the induction of airway hyperresponsiveness (AHR) in a rabbit model of allergic asthma. Relative to non-sensitized animals, OVA-sensitized rabbits challenged with inhaled OVA exhibited AHR, lung inflammation, elevated BAL levels of IL-13, and increased airway phosphodiesterase-4 (PDE4) activity. These proasthmatic responses were suppressed by pretreatment with an inhaled membrane-permeable anti-Gß? blocking peptide, similar to the suppressive effect of glucocorticoid pretreatment. Extended mechanistic studies demonstrated that: 1) corresponding proasthmatic changes in contractility exhibited in isolated airway smooth muscle (ASM) sensitized with serum from OVA-sensitized+challenged rabbits or IL-13 were also Gß?-dependent and mediated by MAPK-upregulated PDE4 activity; and 2) the latter was attributed to Gß?-induced direct stimulation of the non-receptor tyrosine kinase, c-Src, resulting in downstream activation of ERK1/2 and its consequent transcriptional upregulation of PDE4. Collectively, these data are the first to identify that a mechanism involving Gß?-induced direct activation of c-Src, leading to ERK1/2-mediated upregulation of PDE4 activity, plays a decisive role in regulating the induction of AHR and inflammation in a rabbit model of allergic airway disease.