PMID- 22700433 OWN - NLM STAT- MEDLINE DCOM- 20130307 LR - 20211021 IS - 1521-0103 (Electronic) IS - 0022-3565 (Print) IS - 0022-3565 (Linking) VI - 342 IP - 3 DP - 2012 Sep TI - 15-Deoxy-Delta(1)(2),(1)(4)-prostaglandin J(2)-glycerol, a putative metabolite of 2-arachidonyl glycerol and a peroxisome proliferator-activated receptor gamma ligand, modulates nuclear factor of activated T cells. PG - 816-26 LID - 10.1124/jpet.112.193003 [doi] AB - 2-Arachidonyl glycerol (2-AG) is an endogenous arachidonic acid derivative released on demand from membrane precursors. 2-AG-mediated suppression of interleukin (IL)-2 depends on cyclooxygenase 2 (COX-2) metabolism and peroxisome proliferator-activated receptor gamma (PPARgamma) activation. 15-Deoxy-Delta(1)(2),(1)(4)-prostaglandin J(2)-glycerol ester (15d-PGJ(2)-G), a putative COX-2 metabolite of 2-AG, acts as a PPARgamma ligand and produces IL-2 suppression in activated Jurkat T cells, in part, by decreasing nuclear factor of activated T cells (NFAT) transcriptional activity. The objective of the present studies was to investigate the mechanism by which 15d-PGJ(2)-G modulates NFAT activity to suppress IL-2. 15d-PGJ(2)-G treatment decreased phorbol 12-myristate 13-acetate (PMA)/calcium ionophore (I(0))-induced NFAT DNA binding to the human IL-2 promoter and nuclear NFAT2 accumulation. It is noteworthy that 15d-PGJ(2)-G treatment increased active nuclear HDM2 (human homolog of the oncoprotein and E3 ubiquitin ligase murine double minute 2) expression, whereas there was no change in the expression of glycogen synthase kinase 3beta, both of which regulate NFAT. 15d-PGJ(2)-G and other PPARgamma agonists, such as rosiglitazone and ciglitazone, decreased PMA/I(0)-mediated elevation in intracellular calcium concentration ([Ca(2)(+)](i)) in activated Jurkat cells. We were surprised to find that the PPARgamma antagonists 2-chloro-5-nitro-N-4-pyridinylbenzamide (T0070907) and 2-chloro-5-nitrobenzanilide (GW9662) also decreased the PMA/I(0)-mediated elevation in [Ca(2)(+)](i) in activated T cells. In addition, the presence of T0070907 plus 15d-PGJ(2)-G produced an additive decrease in PMA/I(0)-mediated elevation of [Ca(2)(+)](i), suggesting that the 15d-PGJ(2)-G effects on calcium might be either PPARgamma-independent or -dependent on occupation of the PPARgamma ligand binding domain. Collectively, our findings suggest that 15d-PGJ(2)-G increases active nuclear HDM2, which could lead to a decrease in NFAT2 and IL-2 suppression. FAU - Raman, Priyadarshini AU - Raman P AD - Department of Pharmacology and Toxicology and the Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan, USA. FAU - Kaplan, Barbara L F AU - Kaplan BL FAU - Kaminski, Norbert E AU - Kaminski NE LA - eng GR - R01 DA020402/DA/NIDA NIH HHS/United States GR - R01-DA020402/DA/NIDA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20120613 PL - United States TA - J Pharmacol Exp Ther JT - The Journal of pharmacology and experimental therapeutics JID - 0376362 RN - 0 (15-deoxy-delta(12,14)-prostaglandin J2) RN - 0 (Arachidonic Acids) RN - 0 (DNA-Binding Proteins) RN - 0 (Endocannabinoids) RN - 0 (Glycerides) RN - 0 (Interleukin-2) RN - 0 (NFATC Transcription Factors) RN - 0 (PPAR gamma) RN - 8D239QDW64 (glyceryl 2-arachidonate) RN - EC 2.3.2.27 (MDM2 protein, human) RN - EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2) RN - EC 2.7.11.1 (GSK3B protein, human) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.1 (Gsk3b protein, mouse) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) RN - PDC6A3C0OX (Glycerol) RN - RXY07S6CZ2 (Prostaglandin D2) RN - SY7Q814VUP (Calcium) SB - IM MH - Animals MH - Arachidonic Acids/*metabolism MH - Calcium/metabolism MH - Cell Nucleus/drug effects/metabolism MH - DNA-Binding Proteins/metabolism MH - Endocannabinoids/*metabolism MH - Female MH - Glycerides/*metabolism MH - Glycerol/*pharmacology MH - Glycogen Synthase Kinase 3/metabolism MH - Glycogen Synthase Kinase 3 beta MH - Humans MH - Interleukin-2/metabolism MH - Jurkat Cells MH - Lymphocyte Activation MH - Mice MH - NFATC Transcription Factors/*metabolism MH - PPAR gamma/*metabolism MH - Promoter Regions, Genetic MH - Prostaglandin D2/*analogs & derivatives/pharmacology MH - Proto-Oncogene Proteins c-mdm2/metabolism MH - T-Lymphocytes/*drug effects/*metabolism PMC - PMC3422518 EDAT- 2012/06/16 06:00 MHDA- 2013/03/08 06:00 PMCR- 2013/09/01 CRDT- 2012/06/16 06:00 PHST- 2012/06/16 06:00 [entrez] PHST- 2012/06/16 06:00 [pubmed] PHST- 2013/03/08 06:00 [medline] PHST- 2013/09/01 00:00 [pmc-release] AID - jpet.112.193003 [pii] AID - 3789525 [pii] AID - 10.1124/jpet.112.193003 [doi] PST - ppublish SO - J Pharmacol Exp Ther. 2012 Sep;342(3):816-26. doi: 10.1124/jpet.112.193003. Epub 2012 Jun 13.