Abstract
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.
Footnotes
This work was supported by the Sandler Asthma Foundation [Grant 02-0075]; and the National Institutes of Health National Institute on Drug Abuse [R01-DA012413].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/mol.110.070201.
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ABBREVIATIONS:
- PPAR-α
- peroxisome proliferator-activated receptor-α
- PEA
- palmitoylethanolamide
- NAPE-PLD
- N-acylphosphatidylethanolamine-specific phospholipase D
- LPS
- lipopolysaccharide
- HDAC
- histone deacetylase
- NAAA
- N-acylethanolamine-hydrolyzing acid amidase
- FAAH
- fatty-acid amide hydrolase
- FBS
- fetal bovine serum
- PCR
- polymerase chain reaction
- PMSF
- phenylmethylsulfonyl fluoride
- MS
- mass spectrometry
- LC/MS
- liquid chromatography/mass spectrometry
- ChIP
- chromatin immunoprecipitation
- bp
- base pair
- TLR4
- Toll-like receptor-4.
- Received November 28, 2010.
- Accepted January 12, 2011.
- Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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