Received for publication May 11, 2007.
Revised July 25, 2007.
Accepted for publication August 1, 2007.

Inhibition of trail gene expression by cyclopentenonic prostaglandin 15-deoxy-^12,14-PGJ₂ in T lymphocytes

Abstract

15d-PGJ₂ is a cyclopentenonic prostaglandin endowed with powerful anti-inflammatory activities, as shown in animal models of inflammatory/autoimmune diseases, where pharmacological administration of this prostanoid can ameliorate inflammation and local tissue damage, via activation of the nuclear receptor PPAR and/or covalent modifications of cellular proteins. TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily expressed in most of the cells, including those of immune system such as T lymphocytes, where it is upregulated upon antigen-specific stimulation. This cytokine plays an important role in regulating various physiological and immuno-pathological processes, such as immunosurveillance of tumours and tissue destruction associated with different inflammatory and autoimmune diseases. Here, we demonstrate that 15d-PGJ₂ inhibits trail mRNA and protein expression by down-regulating the activity of its promoter in human T lymphocytes. Our data indicate that both the chemically reactive cyclopentenone moiety of 15d-PGJ₂ and the activation of PPAR may be involved in this repressive mechanism. We identified NF-kB as a direct target of the prostanoid. 15d-PGJ₂ significantly decreases the expression and/or DNA binding of c-rel, RelA and p50 transcription factors to the NF-kB1 site of trail promoter. Moreover, 15d-PGJ₂-mediated activation of the transcription factor HSF-1, may contribute to inhibit trail promoter activity in transfected Jurkat T cells. These results suggest that modulation of TRAIL gene expression by 15d-PGJ₂ in T cells may provide a novel pharmacological tool to modify the onset and the progression of specific autoimmune and inflammatory disorders.

Key words: Prostanoid, PPARs, NFkappaB, Regulation of gene expression, Regulation - transcriptional