title: The B subunit of Escherichia coli heat-labile enterotoxin induces both caspase-dependent and -independent cell death pathways in CD8+ T cells.
abstract: The nontoxic B subunit of Escherichia coli heat-labile enterotoxin (EtxB) is a potent immunomodulatory molecule that acts both as an adjuvant and to stimulate immune deviation processes, resulting in the suppression of Th1-associated inflammatory responses. The ability of EtxB to alter immune reactivity is dependent on its ability to modulate immune cell function through binding to cell surface molecules, the principal receptor of which is the ubiquitous GM1-ganglioside. EtxB activates B cells and antigen-presenting cells and induces the selective apoptosis of murine CD8+ T cells. We postulated that these effects are mediated by the induction of intracellular signaling pathways following EtxB-receptor interaction. We have previously shown that CD8+ T-cell apoptosis induced by EtxB results from the activation of the transcription factor NF-kappaB and caspases. Here we report that while caspase activity is required for apoptosis, additional features of cell death are caspase independent. EtxB induces a rapid loss of mitochondrial membrane potential and cell viability that are unaffected by caspase inhibitors. In addition, our data suggest that these processes are independent of the activity of Bax and Bcl-2 but are mediated by nitric oxide synthase.
authors.affiliation: Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Salmond
authors.forename: Rachel
authors.initials: R
authors.lastname: Williams
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Hirst
authors.forename: Neil A
authors.initials: NA
authors.lastname: Williams
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001427:Bacterial Toxins / Q000737:chemistry* / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D004768:Enterotoxins / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004926:Escherichia coli; D029968:Escherichia coli Proteins; D005260:Female; D006146:Guanidines / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D021122:Protein Subunits / Q000737:chemistry* / Q000494:pharmacology*; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018892:Proton-Motive Force / Q000187:drug effects; D051028:bcl-2-Associated X Protein
chemical_list: D001427:Bacterial Toxins; C494827:Bax protein, mouse; D061945:Caspase Inhibitors; D004768:Enterotoxins; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D006146:Guanidines; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D009569:Nitric Oxide; C027538:heat-labile enterotoxin, E coli; D019001:Nitric Oxide Synthase; D020169:Caspases; C004479:pimagedine