G Protein [beta][gamma]-Subunit Signaling Mediates Airway Hyperresponsiveness and Inflammation in Allergic Asthma

Since the G[beta][gamma] 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 G[beta][gamma] signaling in regulating the induction of airway hyperresponsiveness (AHR) in a rabbit m...

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Bibliographic Details
Published in:PloS one 2012-02, Vol.7 (2), p.e32078
Main Authors: Nino, Gustavo, Hu, Aihua, Grunstein, Judith S, McDonough, Joseph, Kreiger, Portia A, Josephson, Maureen B, Choi, John K, Grunstein, Michael M
Format: Article
Language:English
Subjects:
Analysis
Asthma
G proteins
Glucocorticoids
Inflammation
Peptides
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Summary:Since the G[beta][gamma] 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 G[beta][gamma] 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-G[beta][gamma] 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 G[beta][gamma]-dependent and mediated by MAPK-upregulated PDE4 activity; and 2) the latter was attributed to G[beta][gamma]-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 G[beta][gamma]-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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0032078