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Am. J. Respir. Cell Mol. Biol., Volume 24, Number 6, June, 2001 688-693

Peroxisome Proliferator-Activated Receptor-gamma Regulates Airway Epithelial Cell Activation

Angela C. C. Wang, Xinhua Dai, Bao Luu, and Douglas J. Conrad

VA San Diego Healthcare System and the Veterans Medical Research Foundation, Section of Pulmonary and Critical Care; and Department of Medicine, University of California, San Diego, California

The peroxisome proliferator-activated receptors (PPARs) are nuclear hormone transcription factors that regulate genes associated with lipid and glucose metabolism. Recent evidence suggests that PPAR-gamma may also act as a negative immunomodulator. To investigate the potential role of PPAR-gamma in regulating airway inflammation, we characterized the expression and function of PPAR-gamma in airway epithelial cells. Airway epithelial cells constitutively express PPAR-gamma -specific messenger RNA and protein. Further, airway epithelial PPAR-gamma is inducible by interleukin (IL)-4 in NIH-A549 cells. Two PPAR-gamma agonists, the prostaglandin D2 metabolite 15-deoxy-Delta 12,14 prostaglandin J2 (15d-PGJ2) and a thiazolidinedione, ciglitazone, were used to study the effects of PPAR-gamma activation on airway epithelial cytokine expression. Activation of PPAR-gamma stimulated a PPAR-responsive 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, ciglitazone alone had a slight effect on cytokine-induced IL-8 secretion, but markedly inhibited IL-8 secretion from cells pretreated with IL-4. The demonstration of PPAR-gamma expression and function in airway epithelial cells expands the immunoregulatory role of PPARs and suggests a critical role for PPAR-gamma in antagonizing proinflammatory pathways in the airways.

Abbreviations: prostaglandin D2 metabolite 15-deoxy-Delta 12,14 prostaglandin J2, 15d-PGJ2; activator protein, AP; complementary DNA, cDNA; interferon, IFN; interleukin, IL; inducible nitric oxide synthase, iNOS; 12/15- lipoxygenase, 12/15-LO; nuclear factor, NF; peroxisome proliferator-activated receptor, PPAR; tumor necrosis factor, TNF.




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