title: Proinflammatory stimuli control N-acylphosphatidylethanolamine-specific phospholipase D expression in macrophages.
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.
authors.affiliation: Department of Biological Chemistry, University of California, Irvine, California, USA.
authors.forename: Chenggang
authors.initials: C
authors.lastname: Zhu
authors.forename: Carlos
authors.initials: C
authors.lastname: Solorzano
authors.forename: Saurabh
authors.initials: S
authors.lastname: Sahar
authors.forename: Natalia
authors.initials: N
authors.lastname: Realini
authors.forename: Ernest
authors.initials: E
authors.lastname: Fung
authors.forename: Paolo
authors.initials: P
authors.lastname: Sassone-Corsi
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D018836:Inflammation Mediators / Q000633:toxicity*; D008070:Lipopolysaccharides / Q000633:toxicity*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010739:Phospholipase D / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
chemical_list: D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D010739:Phospholipase D; C506062:Napepld protein, mouse