PPAR-gamma modulates allergic inflammation through up-regulation of PTEN

ABSTRACTThe ligand‐activated nuclear receptor peroxisome proliferator‐activated receptor γ (PPARγ) has been shown to regulate cell activation, differentiation, proliferation, and/or apoptosis. PPARγ is also associated with anti‐inflammatory responses. However, the signaling mechanism remains elusive. We have used a mouse model for asthma to determine the effect of PPARγ agonists, rosiglitazone or pioglitazone, and PPARγ on allergen‐induced bronchial inflammation and airway hyperresponsiveness. Administration of PPARγ agonists or adenovirus carrying PPARγ cDNA (AdPPARγ) reduced bronchial inflammation and airway hyperresponsiveness. Expression of PPARγ was increased by ovalbumin (OVA) inhalation, and the increase was further enhanced by the administration of the PPARγ agonists or AdPPARγ. Levels of IL‐4, IL‐5, IL‐13, and eosinophil cationic protein were increased after OVA inhalation, and the increased levels were significantly reduced by the administration of PPARγ agonists or AdPPARγ. The results also showed that the administration of PPARγ agonists or AdPPARγ up‐regulated phosphatase and tensin homologue deleted on chromosome ten (PTEN) expression in allergen‐induced asthmatic lungs. This up‐regulation correlated with decreased phosphatidylinositol 3‐kinase activity as measured by reduced phosphorylation of Akt. These findings demonstrate a protective role of PPARγ in the pathogenesis of the asthma phenotype through regulation of PTEN expression.