Peroxisome proliferator-activated receptor-gamma regulates airway epithelial cell activation

The peroxisome proliferator-activated receptors (PPARs) are nuclear hormone transcription factors that regulate genes associated with lipid and glucos e metabolism. Recent evidence suggests that PPAR-gamma may also act as a ne gative immunomodulator. To investigate the potential role of PPAR-gamma in regulating airway inflammation, we characterized the expression and functio n of PPAR-gamma in airway epithelial cells. Airway epithelial cells constit utively express PPAR-gamma -specific messenger RNA and protein. Further, ai rway epithelial PPAR-gamma is inducible by interleukin (IL)-4 in NIH-A549 c ells. Two PPAR-gamma agonists, the prostaglandin D2 metabolite 15-deoxy-Del ta (12,14) prostaglandin J(2) (15d-PGJ(2)) and a thiazolidinedione, ciglita zone, were used to study the effects of PPAR-gamma activation on airway epi thelial cytokine expression. Activation of PPAR-gamma stimulated a PPAR-res ponsive reporter gene in a ligand-specific manner. In NIH-A549 cells, both ligands also blocked the cytokine-induced expression of the inducible form of nitric oxide synthase in a dose-dependent manner. In contrast, ciglitazo ne alone had a slight effect on cytokine-induced IL-8 secretion, but marked ly inhibited IL-8 secretion from cells pretreated with IL-4. The demonstrat ion of PPAR-gamma expression and function in airway epithelial cells expand s the immunoregulatory role of PPARs and suggests a critical role for PPAR- gamma in antagonizing proinflammatory pathways in the airways.