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: Alessio Nencioni, Kirsten Lauber, Frank Grünebach, Luk Van Parijs, Claudio Denzlinger, Sebastian Wesselborg, Peter Brossart
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 171 Issue 10 Pg. 5148-56 (Nov 15 2003) ISSN: 0022-1767 [Print] United States
• PMID: 14607914 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 15-deoxyprostaglandin J2
• Cyclopentanes
• Growth Inhibitors
• Receptors, Cytoplasmic and Nuclear
• Receptors, Tumor Necrosis Factor
• Thiazolidinediones
• Transcription Factors
• Rosiglitazone
• cyclopentenone
• Prostaglandin D2

Topics

• Apoptosis (drug effects, immunology)
• Cyclopentanes (pharmacology)
• Down-Regulation (drug effects, immunology)
• Growth Inhibitors (pharmacology)
• Humans
• Intracellular Membranes (drug effects, immunology)
• Jurkat Cells
• Lymphocyte Activation (drug effects, immunology)
• Membrane Potentials (drug effects, immunology)
• Mitochondria (drug effects, metabolism, physiology)
• Oxidative Stress (drug effects, immunology)
• Permeability (drug effects)
• Prostaglandin D2 (analogs & derivatives, pharmacology)
• Receptors, Cytoplasmic and Nuclear (agonists, metabolism, physiology)
• Receptors, Tumor Necrosis Factor (physiology)
• Rosiglitazone
• Signal Transduction (drug effects, immunology)
• T-Lymphocyte Subsets (cytology, drug effects, immunology, metabolism)
• Thiazolidinediones (metabolism, pharmacology)
• Transcription Factors (agonists, metabolism, physiology)