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/␦) and PPAR␥ were expressed. 3OC 12 -HSL functioned as an agonist of PPAR/␦ transcriptional activity and an antagonist of PPAR␥ transcriptional activity and inhibited the DNA binding ability of PPAR␥. The proinflammatory effect of 3OC 12 -HSL in lung epithelial cells was blocked by the PPAR␥ agonist rosiglitazone, suggesting that 3OC 12 -HSL and rosiglitazone are mutually antagonistic negative and positive regulators of PPAR␥ activity, respectively. These data identify PPAR/␦ and PPAR␥ as putative mammalian 3OC 12 -HSL receptors and suggest that PPAR␥ agonists may be employed as anti-inflammatory therapeutics for P. aeruginosa infections.
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