Cyclopentenone Prostaglandins Induce Lymphocyte Apoptosis by Activating the Mitochondrial Apoptosis Pathway Independent of External Death Receptor Signaling

15-Deoxy-Δ^12,14-PGJ₂ (15d-PGJ₂) is a naturally occurring cyclopentenone metabolite of PGD₂ that possesses both peroxisome proliferator-activated receptor γ (PPAR-γ)-dependent and PPAR-γ-independent anti-inflammatory properties. Recent studies suggest that cyclopentenone PGs may play a role in the down-regulation of inflammation-induced immune responses. In this study, we report that 15d-PGJ₂ as well as synthetic PPAR-γ agonists inhibit lymphocyte proliferation. However, only 15d-PGJ₂, but not the specific PPAR-γ activators, induce lymphocyte apoptosis. We found that blocking of the death receptor pathway in Fas-associated death domain ^-/- or caspase-8^-/- Jurkat T cells has no effect on apoptosis induction by 15d-PGJ₂. Conversely, overexpression of Bcl-2 or Bcl-x_L completely inhibits the initiation of apoptosis, indicating that 15d-PGJ₂-mediated apoptosis involves activation of the mitochondrial pathway. In line with these results, 15d-PGJ₂ induces mitochondria disassemblage as demonstrated by dissipation of mitochondrial transmembrane potential (Δψ_m) and cytochrome c release. Both of these events are partially inhibited by the broad spectrum caspase inhibitor benzyloxycarbonil-Val-Ala-Asp-fluoromethylketone, suggesting that caspase activation may amplify the mitochondrial alterations initiated by 15d-PGJ₂. We also demonstrate that 15d-PGJ₂ potently stimulates reactive oxygen species production in Jurkat T cells, and Δψ_m loss induced by 15d-PGJ₂ is prevented by the reactive oxygen species scavenger N-acetyl-L-cysteine. In conclusion, our data indicate that cyclopentenone PGs like 15d-PGJ₂ may modulate immune responses even independent of PPAR-γ by activating the mitochondrial apoptosis pathway in lymphocytes in the absence of external death receptor signaling.