NF-kappa B RelA (p65) is essential for TNF-alpha-induced fas expression but dispensable for both TCR-induced expression and activation-induced cell death.
The Fas death receptor plays a key role in the killing of target cells by NK cells and CTLs and in activation-induced cell death of mature T lymphocytes. These cytotoxic pathways are dependent on induction of Fas expression by cytokines such as TNF-alpha and IFN-gamma or by signals generated after TCR engagement. Although much of our knowledge of the Fas death pathway has been generated from murine studies, little is known about regulatory mechanisms important for murine Fas expression. To this end, we have molecularly cloned a region of the murine Fas promoter that is responsible for mediating TNF-alpha and PMA/PHA-induced expression. We demonstrate here that induction of Fas expression by both stimuli is critically dependent on two sites that associate with RelA-containing NF-kappaB complexes. To determine whether RelA and/or other NF-kappaB subunits are also important for regulating Fas expression in primary T cells, we used CD4 T cells from RelA(-/-), c-Rel(-/-), and p50(-/-) mice. Although proliferative responses were significantly impaired, expression of Fas and activation-induced cell death was unaffected in T cells obtained from these different mice. Importantly, we show that unlike fibroblasts, which consist primarily of RelA-containing NF-kappaB complexes, T cells have high levels of both RelA and c-Rel complexes, suggesting that Fas expression in T cells may be dependent on redundant functions of these NF-kappaB subunits.
Zheng
Y
Y
Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Ouaaz
F
F
Bruzzo
P
P
Singh
V
V
Gerondakis
S
S
Beg
A A
AA
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003001:Cloning, Molecular; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D053222:Fas Ligand Protein; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D052002:NF-kappa B p50 Subunit; D010835:Phytohemagglutinins / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000276:immunology; D020569:Proto-Oncogene Proteins c-rel / Q000172:deficiency / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D019014:fas Receptor / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D010835:Phytohemagglutinins; D020569:Proto-Oncogene Proteins c-rel; D011948:Receptors, Antigen, T-Cell; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D013755:Tetradecanoylphorbol Acetate