title: LPS-induced apoptosis is dependent upon mitochondrial dysfunction.
abstract: Bacterial infection induces apoptotic cell death in human monoblastic U937 cells that have been pretreated with interferon gamma (U937IFN). Apoptosis occurs in a manner that is independent of bacterial virulence proteins. In the present study, we show that lipopolysaccharide (LPS), a membrane constituent of gram-negative bacteria, also induces apoptosis in U937IFN cells. LPS treatment led to the appearance of characteristic markers of apoptosis such as nuclear fragmentation and activation of caspases. While the caspase inhibitor Z-VAD-fmk prevented LPS-induced apoptosis as judged by its inhibition of nuclear fragmentation, it failed to inhibit cytochrome c release and loss of mitochondrial membrane potential. Transfection of peptides containing the BH4 (Bcl-2 homology 4) domain derived from the anti-apoptotic protein Bcl-XL blocked LPS-induced nuclear fragmentation and the limited digestion of PARP. These results suggest that LPS does not require caspase activation to induce mitochondrial dysfunction and that mitochondria play a crucial role in the regulation of LPS-mediated apoptosis in U937IFN cells.
authors.affiliation: Department of Basic Medical Science, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kuwabara
authors.forename: S
authors.initials: S
authors.lastname: Imajoh-Ohmi
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D010446:Peptide Fragments / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011112:Polymyxin B / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000502:physiology; D019311:Staurosporine / Q000494:pharmacology; D020298:U937 Cells; D051020:bcl-X Protein; D019014:fas Receptor / Q000276:immunology
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000911:Antibodies, Monoclonal; C494811:BCL2L1 protein, human; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019014:fas Receptor; D007371:Interferon-gamma; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D019311:Staurosporine; D011112:Polymyxin B