PT  - JOURNAL ARTICLE
AU  - Chenggang Zhu
AU  - Carlos Solorzano
AU  - Saurabh Sahar
AU  - Natalia Realini
AU  - Ernest Fung
AU  - Paolo Sassone-Corsi
AU  - Daniele Piomelli
TI  - Proinflammatory stimuli control NAPE-PLD expression in macrophages
AID  - 10.1124/mol.110.070201
DP  - 2011 Jan 01
TA  - Molecular Pharmacology
PG  - mol.110.070201
4099  - http://molpharm.aspetjournals.org/content/early/2011/01/13/mol.110.070201.short
4100  - http://molpharm.aspetjournals.org/content/early/2011/01/13/mol.110.070201.full
AB  - 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 pro-inflammatory 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 pro-inflammatory stimuli suppress NAPE-PLD expression and PEA biosynthesis in macrophages and that this effect might contribute to the inflammatory response.