title: Cyclopentenone prostaglandins induce lymphocyte apoptosis by activating the mitochondrial apoptosis pathway independent of external death receptor signaling.
abstract: 15-Deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) is a naturally occurring cyclopentenone metabolite of PGD(2) that possesses both peroxisome proliferator-activated receptor gamma (PPAR-gamma)-dependent and PPAR-gamma-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-PGJ(2) as well as synthetic PPAR-gamma agonists inhibit lymphocyte proliferation. However, only 15d-PGJ(2), but not the specific PPAR-gamma 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-PGJ(2). Conversely, overexpression of Bcl-2 or Bcl-x(L) completely inhibits the initiation of apoptosis, indicating that 15d-PGJ(2)-mediated apoptosis involves activation of the mitochondrial pathway. In line with these results, 15d-PGJ(2) induces mitochondria disassemblage as demonstrated by dissipation of mitochondrial transmembrane potential (Deltapsi(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-PGJ(2). We also demonstrate that 15d-PGJ(2) potently stimulates reactive oxygen species production in Jurkat T cells, and Deltapsi(m) loss induced by 15d-PGJ(2) is prevented by the reactive oxygen species scavenger N-acetyl-L-cysteine. In conclusion, our data indicate that cyclopentenone PGs like 15d-PGJ(2) may modulate immune responses even independent of PPAR-gamma by activating the mitochondrial apoptosis pathway in lymphocytes in the absence of external death receptor signaling.
authors: Department of Hematology, Oncology and Immunology, University of Tübingen, Tübingen, Germany.
authors: Alessio
authors: A
authors: Nencioni
authors: Kirsten
authors: K
authors: Lauber
authors: Frank
authors: F
authors: Grünebach
authors: Luk
authors: L
authors: Van Parijs
authors: Claudio
authors: C
authors: Denzlinger
authors: Sebastian
authors: S
authors: Wesselborg
authors: Peter
authors: P
authors: Brossart
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D003517:Cyclopentanes / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000276:immunology; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008564:Membrane Potentials / Q000187:drug effects / Q000276:immunology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology; D010539:Permeability / Q000187:drug effects; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D045162:Thiazolidinediones / Q000378:metabolism / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism / Q000502:physiology
chemical_list: C477819:15-deoxyprostaglandin J2; D003517:Cyclopentanes; D006131:Growth Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; C013905:cyclopentenone; D015230:Prostaglandin D2