Peroxisome proliferator-activated receptors mediate host cell proinflammatory responses to Pseudomonas aeruginosa autoinducer

The pathogenic bacterium Pseudomonas aeruginosa utilizes the 3-oxododecanoyl homoserine lactone (3OC(12)-HSL) autoinducer as a signaling molecule to coordinate the expression of virulence genes through quorum sensing. 3OC(12)-HSL also affects responses in host cells, including the upregulation of genes encoding inflammatory cytokines. This proinflammatory response may exacerbate underlying disease during P. aeruginosa infections. The specific mechanism(s) through which 3OC(12)-HSL influences host responses is unclear, and no mammalian receptors for 3OC(12)-HSL have been identified to date. Here, we report that 3OC(12)-HSL increases mRNA levels for a common panel of proinflammatory genes in murine fibroblasts and human lung epithelial cells. To identify putative 3OC(12)-HSL receptors, we examined the expression patterns of a panel of nuclear hormone receptors in these two cell lines and determined that both peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) and PPAR-gamma were expressed. 3OC(12)-HSL functioned as an agonist of PPAR beta/delta transcriptional activity and an antagonist of PPAR gamma transcriptional activity and inhibited the DNA binding ability of PPAR gamma. The proinflammatory effect of 3OC(12)-HSL in lung epithelial cells was blocked by the PPAR gamma agonist rosiglitazone, suggesting that 3OC(12)-HSL and rosiglitazone are mutually antagonistic negative and positive regulators of PPAR gamma activity, respectively. These data identify PPAR beta/delta and PPAR-gamma as putative mammalian 3OC(12)-HSL receptors and suggest that PPAR-gamma agonists may be employed as anti-inflammatory therapeutics for P. aeruginosa infections.