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 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.
Wang
A C
AC
VA San Diego Healthcare System and the Veterans Medical Research Foundation, Section of Pulmonary and Critical Care, San Diego, California, USA.
Dai
X
X
Luu
B
B
Conrad
D J
DJ
D000276:Adjuvants, Immunologic / Q000378:metabolism; D016207:Cytokines; D015536:Down-Regulation; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D015847:Interleukin-4 / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism*; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000276:Adjuvants, Immunologic; D016207:Cytokines; D018836:Inflammation Mediators; D016209:Interleukin-8; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D015847:Interleukin-4; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D015230:Prostaglandin D2; C039671:ciglitazone