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Molecular Pharmacology

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Research ArticleArticle

15-Deoxy-Δ12,14-prostaglandin J2-Glycerol Ester, a Putative Metabolite of 2-Arachidonyl Glycerol, Activates Peroxisome Proliferator Activated Receptor γ

Priyadarshini Raman, Barbara L. F. Kaplan, Jerry T. Thompson, John P. Vanden Heuvel and Norbert E. Kaminski
Molecular Pharmacology July 2011, 80 (1) 201-209; DOI: https://doi.org/10.1124/mol.110.070441
Priyadarshini Raman
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Barbara L. F. Kaplan
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Jerry T. Thompson
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John P. Vanden Heuvel
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Norbert E. Kaminski
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Abstract

2-Arachidonyl glycerol (2-AG) is an endogenous arachidonic acid derivative capable of suppressing interleukin (IL)-2 production by activated T cells. 2-AG-mediated IL-2 suppression is dependent on cyclooxygenase-2 (COX-2) metabolism and peroxisome proliferator activated receptor γ (PPARγ) activation. The objective of the present studies was to examine whether 15-deoxy-Δ12,14-PGJ2-glycerol ester (15d-PGJ2-G), a putative metabolite of 2-AG, can mimic the actions of 2-AG on IL-2 regulation through PPARγ activation. 15d-PGJ2-G bound PPARγ-ligand binding domain in a PPARγ competitive binding assay. 15d-PGJ2-G treatment activated PPARγ in a reporter assay, and PPARγ activation was attenuated when a PPARγ antagonist, 2-chloro-5-nitro-N-4-pyridinylbenzamide (T0070907), was present. 15d-PGJ2-G treatment suppressed IL-2 production by activated Jurkat cells, which was partially attenuated when pretreated with T0070907. Moreover, IL-2 suppression was pronounced when 15d-PGJ2-G was present 30 min before or after T-cell activation. Concordant with IL-2 suppression, 15d-PGJ2-G treatment decreased nuclear factor of activated T cells (NFAT) transcriptional activity in transiently transfected Jurkat cells. It is noteworthy that T0070907 alone markedly increased NFAT reporter activity, suggesting the existence of endogenous PPARγ activation and modulation of NFAT. Because COX-2 metabolism of 2-AG is important for IL-2 suppression, the effect of 2-AG on COX-2 and PPARγ mRNA expression was investigated. 2-AG treatment decreased the up-regulation of COX-2 mRNA after T-cell activation, which suggests negative feedback limiting COX-2-mediated metabolism of 2-AG. PPARγ mRNA expression was increased upon activation, and 2-AG treatment produced a modest decrease in PPARγ mRNA expression. Collectively, our findings suggest that 15d-PGJ2-G activates PPARγ to decrease NFAT transcriptional activity and IL-2 expression in activated T cells.

Footnotes

  • This work was supported in part by the National Institutes of Health National Institute on Drug Abuse [Grant R01-DA12740]; and by a research fellowship from Pfizer Global Research and Development.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.070441.

  • ABBREVIATIONS:

    2-AG
    2-arachidonyl glycerol
    IL-2
    interleukin-2
    COX-2
    cyclooxygenase-2
    PPARγ
    peroxisome proliferator activated receptor γ
    15d-PGJ2-G
    15-deoxy-Δ12,14-PGJ2-glycerol ester
    NFAT
    nuclear factor of activated T cells
    CB1 and CB2
    cannabinoid receptor 1 and 2
    LPS
    lipopolysaccharide
    AEA
    anandamide
    AA
    arachidonic acid
    PG
    prostaglandin
    CGZ
    ciglitazone
    CsA
    cyclosporin A
    IFNγ
    interferon γ
    BSA
    bovine serum albumin.

  • Received December 16, 2010.
  • Accepted April 21, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (1)
Molecular Pharmacology
Vol. 80, Issue 1
1 Jul 2011
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Research ArticleArticle

15-Deoxy-Δ12,14-prostaglandin J2-Glycerol Ester, a Putative Metabolite of 2-Arachidonyl Glycerol, Activates Peroxisome Proliferator Activated Receptor γ

Priyadarshini Raman, Barbara L. F. Kaplan, Jerry T. Thompson, John P. Vanden Heuvel and Norbert E. Kaminski
Molecular Pharmacology July 1, 2011, 80 (1) 201-209; DOI: https://doi.org/10.1124/mol.110.070441

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Research ArticleArticle

15-Deoxy-Δ12,14-prostaglandin J2-Glycerol Ester, a Putative Metabolite of 2-Arachidonyl Glycerol, Activates Peroxisome Proliferator Activated Receptor γ

Priyadarshini Raman, Barbara L. F. Kaplan, Jerry T. Thompson, John P. Vanden Heuvel and Norbert E. Kaminski
Molecular Pharmacology July 1, 2011, 80 (1) 201-209; DOI: https://doi.org/10.1124/mol.110.070441
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