The cyclopentenone-type prostaglandin 15-deoxy-delta12,14-prostaglandin J2 inhibits CD95 ligand gene expression in T lymphocytes: interference with promoter activation via peroxisome proliferator-activated receptor-gamma-independent mechanisms

6533b831fe1ef96bd1299080

RESEARCH PRODUCT

The cyclopentenone-type prostaglandin 15-deoxy-delta12,14-prostaglandin J2 inhibits CD95 ligand gene expression in T lymphocytes: interference with promoter activation via peroxisome proliferator-activated receptor-gamma-independent mechanisms

Cinzia Fionda Marco Cippitelli Aldo Lupo Mario Piccoli Angela Santoni Luigi Frati Danilo Di Bona

subject

Fas Ligand Protein Nerve growth factor IB T-Lymphocytes Immunology Peroxisome proliferator-activated receptor Receptors Cytoplasmic and Nuclear Apoptosis Cyclopentanes Biology Ligands Lymphocyte Activation Jurkat cells Immediate-Early Proteins Transactivation chemistry.chemical_compound Jurkat Cells Mice Heat Shock Transcription Factors Peroxisomes Immunology and Allergy Animals Humans HSP70 Heat-Shock Proteins Gene Silencing fas Receptor Receptor Promoter Regions Genetic Cell Line Transformed Early Growth Response Protein 1 chemistry.chemical_classification Hybridomas Membrane Glycoproteins Prostaglandin D2 Fas receptor Molecular biology DNA-Binding Proteins chemistry Nuclear receptor lipids (amino acids peptides and proteins)Prostaglandin D2 Transcription Factors

description

Abstract 15-Deoxy-Δ12,14-PGJ2 (15d-PGJ2) is a cyclopentenone-type PG endowed with anti-inflammatory properties and produced by different cells, including those of the immune system. 15d-PGJ2 is a natural ligand of the peroxisome proliferator-activated receptor (PPAR)-γ nuclear receptor, but relevant PPARγ-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-PGJ2 on the activation of the fas-L gene in T lymphocytes. We show that 15d-PGJ2 inhibits fas-L mRNA expression, activation-induced cell death, and fas-L promoter activity by mechanisms independent of PPARγ and mediated by its chemically reactive cyclopentenone moiety. Our data indicate that 15d-PGJ2 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-κB, 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-PGJ2. These results suggest that modulation of Fas-L by 15d-PGJ2 in T cells may represent an additional tool to consider for treatment of specific autoimmune and inflammatory disorders.

year	journal	country	edition	language
2003-04-23

http://hdl.handle.net/11573/362184