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J Immunol ; 167(6): 3164-73, 2001 Sep 15.
Article in English | MEDLINE | ID: mdl-11544302

ABSTRACT

The NF-kappaB family of transcription factors functions broadly in the host control of immunoregulatory gene expression, inflammation, and apoptosis. Using Jurkat T cells engineered to inducibly express a transdominant repressor of IkappaBalpha, we examined the role of NF-kappaB in the regulation of cytokine and apoptotic gene expression. In this T cell model, as well as in primary T lymphocytes, expression of TNF-related apoptosis-inducing ligand (TRAIL) apoptotic signaling protein was dramatically down-regulated by inhibition of NF-kappaB binding activity. TRAIL acts through membrane death receptors to induce apoptosis of activated T lymphocytes and can be up-regulated by a variety of physiological and pharmacological inducers. However, regulation of TRAIL gene expression has not been defined. Treatment with TCR mimetics (PMA/ionomycin, PHA, and anti-CD3/CD28 Abs) resulted in a rapid increase in the expression of TRAIL mRNA and cell surface TRAIL protein. Induction of the transdominant repressor of IkappaBalpha dramatically down-regulated surface expression of TRAIL, indicating an essential role for NF-kappaB in the regulation of TRAIL. The induced expression of TRAIL was linked to a c-Rel binding site in the proximal TRAIL promoter at position -256 to -265; mutation of this site or an adjacent kappaB site resulted in a complete loss of the inducibility of the TRAIL promoter. The regulation of TRAIL expression by NF-kappaB may represent a general mechanism that contributes to the control of TRAIL-mediated apoptosis in T lymphocytes.


Subject(s)
Apoptosis/drug effects , DNA-Binding Proteins/physiology , Gene Expression Regulation/drug effects , I-kappa B Proteins , Membrane Glycoproteins/biosynthesis , NF-kappa B/physiology , T-Lymphocytes/drug effects , Transcription, Genetic/drug effects , Tumor Necrosis Factor-alpha/biosynthesis , Amino Acid Substitution , Antibodies, Monoclonal/pharmacology , Apoptosis/genetics , Apoptosis Regulatory Proteins , CD28 Antigens/immunology , CD3 Complex/immunology , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/genetics , Gene Expression Regulation, Neoplastic/drug effects , Humans , Ionomycin/pharmacology , Jurkat Cells , Membrane Glycoproteins/genetics , Mutagenesis, Site-Directed , NF-KappaB Inhibitor alpha , NF-kappa B/antagonists & inhibitors , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Phytohemagglutinins/pharmacology , Promoter Regions, Genetic , Proto-Oncogene Proteins c-rel/metabolism , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , RNA, Neoplasm/biosynthesis , RNA, Neoplasm/genetics , Recombinant Fusion Proteins/physiology , T-Lymphocytes/metabolism , TNF-Related Apoptosis-Inducing Ligand , Tetradecanoylphorbol Acetate/pharmacology , Transfection , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/physiology
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