15-Deoxy-Δ¹²,¹⁴-prostaglandin J₂-glycerol, a putative metabolite of 2-arachidonyl glycerol and a peroxisome proliferator-activated receptor γ ligand, modulates nuclear factor of activated T cells.
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 γ (PPARγ) activation. 15-Deoxy-Δ¹²,¹⁴-prostaglandin J₂-glycerol ester (15d-PGJ₂-G), a putative COX-2 metabolite of 2-AG, acts as a PPARγ 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-PGJ₂-G modulates NFAT activity to suppress IL-2. 15d-PGJ₂-G treatment decreased phorbol 12-myristate 13-acetate (PMA)/calcium ionophore (I₀)-induced NFAT DNA binding to the human IL-2 promoter and nuclear NFAT2 accumulation. It is noteworthy that 15d-PGJ₂-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 3β, both of which regulate NFAT. 15d-PGJ₂-G and other PPARγ agonists, such as rosiglitazone and ciglitazone, decreased PMA/I₀-mediated elevation in intracellular calcium concentration ([Ca²⁺](i)) in activated Jurkat cells. We were surprised to find that the PPARγ antagonists 2-chloro-5-nitro-N-4-pyridinylbenzamide (T0070907) and 2-chloro-5-nitrobenzanilide (GW9662) also decreased the PMA/I₀-mediated elevation in [Ca²⁺](i) in activated T cells. In addition, the presence of T0070907 plus 15d-PGJ₂-G produced an additive decrease in PMA/I₀-mediated elevation of [Ca²⁺](i), suggesting that the 15d-PGJ₂-G effects on calcium might be either PPARγ-independent or -dependent on occupation of the PPARγ ligand binding domain. Collectively, our findings suggest that 15d-PGJ₂-G increases active nuclear HDM2, which could lead to a decrease in NFAT2 and IL-2 suppression.
Department of Pharmacology and Toxicology and the Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan, USA.
Priyadarshini
P
Raman
Barbara L F
BL
Kaplan
Norbert E
NE
Kaminski
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D063388:Endocannabinoids / Q000378:metabolism*; D005260:Female; D005989:Glycerides / Q000378:metabolism*; D005990:Glycerol / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D001095:Arachidonic Acids; D004268:DNA-Binding Proteins; D063388:Endocannabinoids; D005989:Glycerides; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D047495:PPAR gamma; C094503:glyceryl 2-arachidonate; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D005990:Glycerol; D015230:Prostaglandin D2; D002118:Calcium