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,
*
Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University "La Sapienza," Rome, Italy;
Laboratory of Pathophysiology, Regina Elena Cancer Institute, Rome, Italy;
Istituto Mediterraneo di Neuroscienze "Neuromed," Pozzilli, Italy; and
Dipartimento di Biopatologia e Metodologie Biomediche, University of Palermo, Palermo, Italy
Fas (APO-1/CD95) and its ligand (FasL/CD95L) are cell surface
proteins whose interaction activates apoptosis of Fas-expressing
targets. In T lymphocytes, the Fas/FasL system regulates
activation-induced cell death, a fundamental mechanism for negative
selection of immature T cells in the thymus and for maintenance of
peripheral tolerance. Aberrant expression of Fas and FasL has also been
implicated in diseases in which the lymphocyte homeostasis is
compromised, and several studies have described the pathogenic
functions of Fas and FasL in vivo, particularly in the
induction/regulation of organ-specific autoimmune diseases. The
1,25(OH)2D3 is a secosteroid hormone that
activates the nuclear receptor vitamin D3 receptor (VDR),
whose immunosuppressive activities have been well studied in different
models of autoimmune disease and in experimental organ transplantation.
We and others have recently described the molecular mechanisms
responsible for the negative regulation of the IFN-
and IL-12 genes by
1,25(OH)2D3 in activated T lymphocytes and
macrophages/dendritic cells. In this study, we describe the effect of
1,25(OH)2D3 on the activation of the
fasL gene in T lymphocytes. We show that
1,25(OH)2D3 inhibits activation-induced cell
death, fasL mRNA expression, and that
1,25(OH)2D3-activated VDR represses
fasL promoter activity by a mechanism dependent on the
presence of a functional VDR DNA-binding domain and ligand-dependent
transcriptional activation domain (AF-2). Moreover, we identified a
minimal region of the promoter containing the transcription start site
and a noncanonical c-Myc-binding element, which mediates this
repression. These results place FasL as a novel target for the
immunoregulatory activities of 1,25(OH)2D3, and
confirm the interest for a possible pharmacological use of this
molecule and its derivatives.
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