The cyclopentenone-type prostaglandin 15-deoxy-delta 12,14-prostaglandin J2 inhibits CD95 ligand gene expression in T lymphocytes: interference with promoter activation via peroxisome proliferator-activated receptor-gamma-independent mechanisms.
15-Deoxy-delta(12,14)-PGJ(2) (15d-PGJ(2)) is a cyclopentenone-type PG endowed with anti-inflammatory properties and produced by different cells, including those of the immune system. 15d-PGJ(2) is a natural ligand of the peroxisome proliferator-activated receptor (PPAR)-gamma nuclear receptor, but relevant PPARgamma-independent actions mediated by this prostanoid have been described. Fas (APO-1/CD95) and its ligand (Fas-L) are cell surface proteins whose interaction activates apoptosis of Fas-expressing targets. In T cells, the Fas-Fas-L system regulates activation-induced cell death and has been implicated in diseases in which lymphocyte homeostasis is compromised. Moreover, several studies have described the pathogenic functions of Fas and Fas-L in vivo, particularly in the induction-progression of organ-specific autoimmune diseases. In this study we describe the effect of 15d-PGJ(2) on the activation of the fas-L gene in T lymphocytes. We show that 15d-PGJ(2) inhibits fas-L mRNA expression, activation-induced cell death, and fas-L promoter activity by mechanisms independent of PPARgamma and mediated by its chemically reactive cyclopentenone moiety. Our data indicate that 15d-PGJ(2) may repress fas-L activation by interfering with the expression and/or transcriptional activity of different transcription factors (early growth response types 3 and 1, NF-kappaB, AP-1, c-Myc, Nur77) whose altered balancing and transactivation may contribute for overall repression of this gene. In addition, the activation/expression of the heat shock response genes HSF-1 and HSP70 is not directly involved in the repression, and the electrophilic molecule cyclopentenone (2-cyclopenten-1-one) may reproduce the effects mediated by 15d-PGJ(2). These results suggest that modulation of Fas-L by 15d-PGJ(2) in T cells may represent an additional tool to consider for treatment of specific autoimmune and inflammatory disorders.
Cippitelli
Marco
M
Dipartimento di Medicina Sperimentale e Patologia, Istituto Pasteur-Fondazione Cenci Bolognetti, University La Sapienza, Rome, Italy.
Fionda
Cinzia
C
Di Bona
Danilo
D
Lupo
Aldo
A
Piccoli
Mario
M
Frati
Luigi
L
Santoni
Angela
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002461:Cell Line, Transformed; D003517:Cyclopentanes / Q000737:chemistry / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D051766:Early Growth Response Protein 1; D053222:Fas Ligand Protein; D020868:Gene Silencing / Q000187:drug effects / Q000276:immunology*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000502:physiology; D000076249:Heat Shock Transcription Factors; D006801:Humans; D006825:Hybridomas; D017874:Immediate-Early Proteins; D019169:Jurkat Cells; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D020675:Peroxisomes / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000276:immunology*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D019014:fas Receptor / Q000378:metabolism*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D003517:Cyclopentanes; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D017874:Immediate-Early Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D019014:fas Receptor; C013905:cyclopentenone; D015230:Prostaglandin D2