RT Journal Article
SR Electronic
T1 Proinflammatory Stimuli Control <em>N</em>-Acylphosphatidylethanolamine-Specific Phospholipase D Expression in Macrophages
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 786
OP 792
DO 10.1124/mol.110.070201
VO 79
IS 4
A1 Chenggang Zhu
A1 Carlos Solorzano
A1 Saurabh Sahar
A1 Natalia Realini
A1 Ernest Fung
A1 Paolo Sassone-Corsi
A1 Daniele Piomelli
YR 2011
UL http://molpharm.aspetjournals.org/content/79/4/786.abstract
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 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.