The ligand-activated nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) has been shown to regulate cell activation, differentiation, proliferation, and/or apoptosis. PPARgamma 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 PPARgamma agonists, rosiglitazone or pioglitazone, and PPARgamma on allergen-induced bronchial inflammation and airway hyperresponsiveness. Administration of PPARgamma agonists or adenovirus carrying PPARgamma cDNA (AdPPARgamma) reduced bronchial inflammation and airway hyperresponsiveness. Expression of PPARgamma was increased by ovalbumin (OVA) inhalation, and the increase was further enhanced by the administration of the PPARgamma agonists or AdPPARgamma. 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 PPARgamma agonists or AdPPARgamma. The results also showed that the administration of PPARgamma agonists or AdPPARgamma 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 PPARgamma in the pathogenesis of the asthma phenotype through regulation of PTEN expression.