RT Journal Article
SR Electronic
T1 15-deoxy Δ12,14 PGJ2-glycerol ester, a putative metabolite of 2-arachidonyl glycerol, activates peroxisome proliferator activated receptor γ
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.110.070441
DO 10.1124/mol.110.070441
A1 Priyadarshini Raman
A1 Barbara L. F. Kaplan
A1 Jerry T. Thompson
A1 John P. Vanden Heuvel
A1 Norbert E. Kaminski
YR 2011
UL http://molpharm.aspetjournals.org/content/early/2011/04/21/mol.110.070441.abstract
AB 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 if 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-LBD in a PPARγ competitive binding assay. 15dPGJ2-G treatment activated PPARγ in a reporter assay, which was attenuated when a PPARγ antagonist, 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 either 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. Interestingly, 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 upregulation of COX-2 mRNA following 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.