Inhibition of trail gene expression by cyclopentenonic prostaglandin 15-deoxy-delta12,14-prostaglandin J2 in T lymphocytes.
15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) 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 peroxisome proliferator-activated receptor gamma (PPARgamma) and/or covalent modifications of cellular proteins. Tumor necrosis factor (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, in which it is up-regulated upon antigen-specific stimulation. This cytokine plays an important role in regulating various physiological and immunopathological processes, such as immunosurveillance of tumors and tissue destruction associated with different inflammatory and autoimmune diseases. Here, we demonstrate that 15d-PGJ(2) 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-PGJ(2) and the activation of PPARgamma may be involved in this repressive mechanism. We identified nuclear factor kappaB (NF-kappaB) as a direct target of the prostanoid. 15d-PGJ(2) significantly decreases the expression and/or DNA binding of c-rel, RelA, and p50 transcription factors to the NF-kappaB1 site of trail promoter. Moreover, 15d-PGJ(2)-mediated activation of the transcription factor heat shock factor-1 may contribute to inhibit trail promoter activity in transfected Jurkat T cells. These results suggest that modulation of TRAIL gene expression by 15d-PGJ(2) in T cells may provide a novel pharmacological tool to modify the onset and the progression of specific autoimmune and inflammatory disorders.
Fionda
Cinzia
C
Department of Experimental Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, University La Sapienza, Viale Regina Elena 324, 00161, Rome, Italy.
Nappi
Filomena
F
Piccoli
Mario
M
Frati
Luigi
L
Santoni
Angela
A
Cippitelli
Marco
M
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D000076249:Heat Shock Transcription Factors; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D047495:PPAR gamma / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors* / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000893:Anti-Inflammatory Agents; D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; D007155:Immunologic Factors; D047495:PPAR gamma; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; D014157:Transcription Factors; D015230:Prostaglandin D2