G Protein ßγ-subunit signaling mediates airway hyperresponsiveness and inflammation in allergic asthma.
PLoS One
; 7(2): e32078, 2012.
Article
em En
| MEDLINE
| ID: mdl-22384144
ABSTRACT
Since the Gßγ 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 Gßγ 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-Gßγ 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 Gßγ-dependent and mediated by MAPK-upregulated PDE4 activity; and 2) the latter was attributed to Gßγ-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 Gßγ-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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Asma
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Subunidades beta da Proteína de Ligação ao GTP
/
Subunidades gama da Proteína de Ligação ao GTP
/
Hipersensibilidade
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Hipersensibilidade Imediata
Limite:
Animals
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Humans
/
Male
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article