15-Deoxy-delta12,14-prostaglandin J2-glycerol ester, a putative metabolite of 2-arachidonyl glycerol, activates peroxisome proliferator activated receptor gamma.

摘要

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 gamma (PPARgamma) activation. The objective of the present studies was to examine whether 15-deoxy-Delta(12,14)-PGJ(2)-glycerol ester (15d-PGJ(2)-G), a putative metabolite of 2-AG, can mimic the actions of 2-AG on IL-2 regulation through PPARgamma activation. 15d-PGJ(2)-G bound PPARgamma-ligand binding domain in a PPARgamma competitive binding assay. 15d-PGJ(2)-G treatment activated PPARgamma in a reporter assay, and PPARgamma activation was attenuated when a PPARgamma antagonist, 2-chloro-5-nitro-N-4-pyridinylbenzamide (T0070907), was present. 15d-PGJ(2)-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-PGJ(2)-G was present 30 min before or after T-cell activation. Concordant with IL-2 suppression, 15d-PGJ(2)-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 PPARgamma 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 PPARgamma 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. PPARgamma mRNA expression was increased upon activation, and 2-AG treatment produced a modest decrease in PPARgamma mRNA expression. Collectively, our findings suggest that 15d-PGJ(2)-G activates PPARgamma to decrease NFAT transcriptional activity and IL-2 expression in activated T cells.