Abstract
Since the Gβγ 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 Gβγ 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-Gβγ 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 Gβγ-dependent and mediated by MAPK-upregulated PDE4 activity; and 2) the latter was attributed to Gβγ-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 Gβγ-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.
Highlights
G proteins play critical roles in regulating the allergic asthmatic phenotype, including the induction of airway hyperresponsiveness (AHR) and inflammation [1]
The results obtained in studies conducted in an in vivo rabbit model of allergic asthma and in isolated atopic sensitized airway smooth muscle (ASM) tissues are the first to demonstrate that: 1) inhibition of Gbc signaling prevents the induction of airway hyperresponsiveness and inflammation elicited by antigen challenge in allergic rabbits, as well as the proasthmatic changes in constrictor and relaxation responsiveness exhibited in atopic sensitized ASM tissues; and 2) these bronchoprotective actions of Gbc inhibition are attributed to suppression of Gbc-induced direct activation of c-Src, which leads to downstream ERK1/2-dependent upregulation of PDE4 activity and its consequent pro-asthmatic effects on airway function
Given recent evidence demonstrating that transcriptional upregulation of PDE4 activity due to Gi-bc-regulated activation of ERK1/2 mediates proasthmatic changes in agonist responsiveness in b2AR-desensitized ASM [10,11,23], we initially examined whether these signaling molecules participate in mediating the reported IgE-induced Gi protein-dependent proasthmatic changes in responsiveness exhibited in ASM tissues passively sensitized with atopic asthmatic serum [7,24]
Summary
G proteins play critical roles in regulating the allergic asthmatic phenotype, including the induction of airway hyperresponsiveness (AHR) and inflammation [1]. The results obtained in studies conducted in an in vivo rabbit model of allergic asthma and in isolated atopic sensitized ASM tissues are the first to demonstrate that: 1) inhibition of Gbc signaling prevents the induction of airway hyperresponsiveness and inflammation elicited by antigen challenge in allergic rabbits, as well as the proasthmatic changes in constrictor and relaxation responsiveness exhibited in atopic sensitized ASM tissues; and 2) these bronchoprotective actions of Gbc inhibition are attributed to suppression of Gbc-induced direct activation of c-Src, which leads to downstream ERK1/2-dependent upregulation of PDE4 activity and its consequent pro-asthmatic effects on airway function Taken together, these new findings highlight a heretoforeunidentified pivotal role for Gbc signaling in regulating the airway asthmatic phenotype, and suggest that interventions targeted at suppressing Gbc signaling associated with Gi protein activation may lead to new approaches to treat allergic airway disease
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