title: LPS induces apoptosis in macrophages mostly through the autocrine production of TNF-alpha.
abstract: The deleterious effects of lipopolysaccharide (LPS) during endotoxic shock are associated with the secretion of tumor necrosis factor (TNF) and the production of nitric oxide (NO), both predominantly released by tissue macrophages. We analyzed the mechanism by which LPS induces apoptosis in bone marrow-derived macrophages (BMDM). LPS-induced apoptosis reached a plateau at about 6 hours of stimulation, whereas the production of NO by the inducible NO-synthase (iNOS) required between 12 and 24 hours. Furthermore, LPS-induced early apoptosis was only moderately reduced in the presence of an inhibitor of iNOS or when using macrophages from iNOS -/-mice. In contrast, early apoptosis was paralleled by the rapid secretion of TNF and was almost absent in macrophages from mice deficient for one (p55) or both (p55 and p75) TNF-receptors. During the late phase of apoptosis (12-24 hours) NO significantly contributed to the death of macrophages even in the absence of TNF-receptor signaling. NO-mediated cell death, but not apoptosis induced by TNF, correlated with the induction of p53 and Bax genes. Thus, LPS-induced apoptosis results from 2 independent mechanisms: first and predominantly, through the autocrine secretion of TNF-alpha (early apoptotic events), and second, through the production of NO (late phase of apoptosis). (Blood. 2000;95:3823-3831)
authors.affiliation: Departament de Fisiologia (Biologia del Macròfag) and Fundació August Pi i Sunyer, Campus de Bellvitge, Facultat de Biologia Universitat de Barcelona, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Xaus
authors.forename: M
authors.initials: M
authors.lastname: Comalada
authors.forename: A F
authors.initials: AF
authors.lastname: Valledor
authors.forename: J
authors.initials: J
authors.lastname: Lloberas
authors.forename: F
authors.initials: F
authors.lastname: López-Soriano
authors.forename: J M
authors.initials: JM
authors.lastname: Argilés
authors.forename: C
authors.initials: C
authors.lastname: Bogdan
authors.forename: A
authors.initials: A
authors.lastname: Celada
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology; D053938:DNA Fragmentation; D016158:Genes, p53; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D026423:S-Nitroso-N-Acetylpenicillamine; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D051028:bcl-2-Associated X Protein
chemical_list: D015703:Antigens, CD; C494827:Bax protein, mouse; D008070:Lipopolysaccharides; D020030:Nitric Oxide Donors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D016173:Macrophage Colony-Stimulating Factor; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D010396:Penicillamine