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Molecular Pharmacology

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Research ArticleArticle

Proinflammatory Stimuli Control N-Acylphosphatidylethanolamine-Specific Phospholipase D Expression in Macrophages

Chenggang Zhu, Carlos Solorzano, Saurabh Sahar, Natalia Realini, Ernest Fung, Paolo Sassone-Corsi and Daniele Piomelli
Molecular Pharmacology April 2011, 79 (4) 786-792; DOI: https://doi.org/10.1124/mol.110.070201
Chenggang Zhu
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Carlos Solorzano
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Saurabh Sahar
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Natalia Realini
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Ernest Fung
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Paolo Sassone-Corsi
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Daniele Piomelli
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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.

  • 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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Molecular Pharmacology: 79 (4)
Molecular Pharmacology
Vol. 79, Issue 4
1 Apr 2011
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Research ArticleArticle

Proinflammatory Stimuli Control N-Acylphosphatidylethanolamine-Specific Phospholipase D Expression in Macrophages

Chenggang Zhu, Carlos Solorzano, Saurabh Sahar, Natalia Realini, Ernest Fung, Paolo Sassone-Corsi and Daniele Piomelli
Molecular Pharmacology April 1, 2011, 79 (4) 786-792; DOI: https://doi.org/10.1124/mol.110.070201

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Research ArticleArticle

Proinflammatory Stimuli Control N-Acylphosphatidylethanolamine-Specific Phospholipase D Expression in Macrophages

Chenggang Zhu, Carlos Solorzano, Saurabh Sahar, Natalia Realini, Ernest Fung, Paolo Sassone-Corsi and Daniele Piomelli
Molecular Pharmacology April 1, 2011, 79 (4) 786-792; DOI: https://doi.org/10.1124/mol.110.070201
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