Prostaglandin D2, its metabolite 15‐d‐PGJ2, and peroxisome proliferator activated receptor‐γ agonists induce apoptosis in transformed, but not normal, human T lineage cells

Abstract

Prostaglandin D₂ (PGD₂) is abundantly produced by mast cells, platelets, and alveolar macrophages and has been proposed as a key immunoregulatory lipid mediator. 15-Deoxy-Δ^12,14-PGJ₂ (15-d-PGJ₂), a key PGD₂ metabolite, is under intense study as a potential anti-inflammatory mediator. Little is known about PGD₂ or the role of 15-d-PGJ₂, if any, in regulating the activities of human T lineage cells. In this report we demonstrate that both PGD₂ and 15-d-PGJ₂ have potent antiproliferative effects, and in fact kill human T lymphocyte lines derived from malignant cells by an apoptotic mechanism. Interestingly, normal human T cells were not similarly affected. Although the T lymphocyte lines express mRNA for the PGD₂ receptor (DP-R), a potent DP receptor agonist, BW245C, did not inhibit the proliferation or viability of the cells, suggesting an alternative mechanism of action. PGD₂ and 15-d-PGJ₂ can bind to the peroxisome proliferator activated receptor-γ (PPAR-γ) which is implicated in lipid metabolism and apoptosis. Exposure to synthetic PPAR-γ ligands (e.g. ciglitazone, troglitazone) mimicked the inhibitory responses of PGD₂ and 15-d-PGJ₂, and induced apoptosis in the transformed T cells consistent with a PPAR-γ-dependent mechanism. These observations suggest that PPAR-γ ligands (which may include PGD₂) provide strong apoptotic signals to transformed, but not normal T lymphocytes. Thus, the efficacy of utilizing PPAR-γ and its ligands as therapeutics for human T cell cancers needs to be further evaluated.