TY - JOUR T1 - Proinflammatory Stimuli Control <em>N</em>-Acylphosphatidylethanolamine-Specific Phospholipase D Expression in Macrophages JF - Molecular Pharmacology JO - Mol Pharmacol SP - 786 LP - 792 DO - 10.1124/mol.110.070201 VL - 79 IS - 4 AU - Chenggang Zhu AU - Carlos Solorzano AU - Saurabh Sahar AU - Natalia Realini AU - Ernest Fung AU - Paolo Sassone-Corsi AU - Daniele Piomelli Y1 - 2011/04/01 UR - http://molpharm.aspetjournals.org/content/79/4/786.abstract N2 - Palmitoylethanolamide (PEA) is an endogenous lipid amide that modulates pain and inflammation by engaging peroxisome proliferator-activated receptor type-α. Here, we show that the proinflammatory bacterial endotoxin lipopolysaccharide (LPS) decreases PEA biosynthesis in RAW264.7 macrophages by suppressing the transcription of N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD), which catalyzes the production of PEA and other lipid amides. Using a luciferase reporter construct and chromatin immunoprecipitation, we further show that LPS treatment reduces acetylation of histone proteins bound to the NAPE-PLD promoter, an effect that is blocked by the histone deacetylase inhibitor trichostatin A. The transcription factor Sp1 is involved in regulating baseline NAPE-PLD expression but not in the transcriptional suppression induced by LPS. The ability of LPS to down-regulate PEA biosynthesis is impaired in peritoneal macrophages from mutant NAPE-PLD-deficient mice, in which PEA is produced through a compensatory mechanism distinct from NAPE-PLD. Moreover, NAPE-PLD-deficient mice fail to mount a normal inflammatory reaction in response to carrageenan administration in vivo. Our findings suggest that proinflammatory stimuli suppress NAPE-PLD expression and PEA biosynthesis in macrophages and that this effect might contribute to the inflammatory response. ER -