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Departments of
*
Hematology, Oncology and Immunology, and
Internal Medicine I, University of Tübingen, Tübingen, Germany; and
Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139
15-Deoxy-
12,14-PGJ2 (15d-PGJ2) is a naturally occurring cyclopentenone metabolite of PGD2 that possesses both peroxisome proliferator-activated receptor 
(PPAR-)-dependent and PPAR--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- agonists inhibit lymphocyte proliferation. However, only 15d-PGJ2, but not the specific PPAR- 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-xL 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 (
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 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- by activating the mitochondrial apoptosis pathway in lymphocytes in the absence of external death receptor signaling.
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