CoChat
Sign Up
Cited by 331Immune Response and InflammationCell death mechanisms and regulationPhagocytosis and Immune Regulation

The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.

LPS induces apoptosis in macrophages mostly through the autocrine production of TNF-α

Xaus, Jordi, Comalada, Mònica, Valledor, Annabel F., Lloberas, Jorge, López-Soriano, Francisco, Argilés, Josep M., Bogdan, Christian, Celada, Antonio·2000·Blood
DOI 10.1182/blood.v95.12.3823
Open this paper in CoChat — free account

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)

Overview

Integrity signals

Registry

Crossref · 10.1182/blood.v95.12.3823

Cites

4 of 4 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Verification

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Citations

Cites

Research works printed but not linked: 74

  1. Ogawa, 1993, Differentiation and proliferation of hematopoietic stem cells., Blood., 81, 2844, 10.1182/blood.V81.11.2844.2844 · DOI
  2. Valledor, 1998, Transcription factors that regulate monocyte/macrophage differentiation., J Leukoc Biol., 63, 405, 10.1002/jlb.63.4.405 · DOI
  3. Celada, 1994, Macrophage activation revisited., Immunol Today., 15, 100, 10.1016/0167-5699(94)90150-3 · DOI
  4. Schereiber, 1985, Monoclonal antibodies to murine gamma-interferon which differentially modulate macrophage activation and antiviral activity., J Immunol., 134, 1609, 10.4049/jimmunol.134.3.1609 · DOI
  5. Morrison, 1987, Endotoxins and disease mechanisms., Ann Rev Med., 38, 417, 10.1146/annurev.me.38.020187.002221 · DOI
  6. Bone, 1991, Sepsis, the sepsis syndrome, multi-organ failure: a plea for comparable definitions., Ann Int Med., 114, 332, 10.7326/0003-4819-114-4-332 · DOI
  7. Marsh, 1996, The pathogenesis of sepsis. Factors that modulate the response to gram-negative bacterial infection., Clin Chest Med., 17, 183, 10.1016/S0272-5231(05)70308-7 · DOI
  8. Salkowski, 1995, Effect of liposome-mediated macrophage depletion on LPS-induced cytokine gene expression and radioprotection., J Immunol., 155, 3168, 10.4049/jimmunol.155.6.3168 · DOI
  9. Petros, 1991, Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock., Lancet., 338, 1557, 10.1016/0140-6736(91)92376-D · DOI
  10. Beutler, 1988, Tumor necrosis, cachexia, shock, and inflammation: a common mediator., Annu Rev Biochem., 57, 505, 10.1146/annurev.bi.57.070188.002445 · DOI
  11. Parrillo, 1993, Pathogenic mechanisms of septic shock., N Engl J Med., 328, 1471, 10.1056/NEJM199305203282008 · DOI · Paper page
  12. Parker, 1987, Serial cardiovascular variables in survivors and nonsurvivors of human septic shock: heart rate as an early predictor of prognosis., Crit Care Med., 15, 923, 10.1097/00003246-198710000-00006 · DOI
  13. Natanson, 1994, Selected treatment strategies for septic shock based on proposed mechanisms of pathogenesis., Annu Intern Med., 120, 771, 10.7326/0003-4819-120-9-199405010-00009 · DOI
  14. Finkel, 1992, Negative inotropic effects of cytokines on the heart mediated by nitric oxide., Science., 257, 387, 10.1126/science.1631560 · DOI
  15. Thiemermann, 1994, The role of the l-arginine: nitric oxide pathway in circulatory shock., Adv Pharmacol., 28, 45, 10.1016/S1054-3589(08)60493-7 · DOI
  16. Hom, 1995, Lipopolysaccharide-induced hypotension and vascular hyporeactivity in the rat: tissue analysis of nitric oxide synthase mRNA and protein expression in the presence and absence of dexamethasone, NG-monomethyl-l-arginine or indomethacin., J Pharmacol Exp Ther., 272, 452
  17. MacMicking, 1995, Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase., Cell., 81, 641, 10.1016/0092-8674(95)90085-3 · DOI
  18. Laubach, 1995, Mice lacking inducible nitric oxide synthase are not resistant to lipopolysaccharide-induced death., Proc Natl Acad Sci U S A., 92, 10688, 10.1073/pnas.92.23.10688 · DOI
  19. Wei, 1995, Altered immune responses in mice lacking inducible nitric oxide synthase., Nature., 375, 408, 10.1038/375408a0 · DOI
  20. Evans, 1994, Inhibition of nitric oxide synthase in experimental gram-negative sepsis., J Infect Dis., 169, 343, 10.1093/infdis/169.2.343 · DOI
  21. Kilburn, 1990, Reversal of endotoxin-mediated shock by NG-methyl-l-arginine, an inhibitor of nitric oxide synthesis., Biochem Biophys Res Commun., 172, 1132, 10.1016/0006-291X(90)91565-A · DOI
  22. Szabo, 1994, Beneficial effects and improved survival in rodent models of septic shock with S-methylisothiurea sulfate, a potent and selective inhibitor of inducible nitric oxide synthase., Proc Natl Acad Sci U S A., 91, 12472, 10.1073/pnas.91.26.12472 · DOI
  23. Minnard, 1994, Inhibition of nitric oxide synthesis is detrimental during endotoxemia., Arch Surg., 129, 142, 10.1001/archsurg.1994.01420260038004 · DOI
  24. Beutler, 1989, The biology of cachectin/TNF-α primary mediator of the host response., Annu Rev Immunol., 7, 625, 10.1146/annurev.iy.07.040189.003205 · DOI
  25. Vasalli, 1992, The pathophysiology of tumor necrosis factor., Annu Rev Immunol., 10, 411, 10.1146/annurev.iy.10.040192.002211 · DOI
  26. Beutler, 1985, Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin., Science., 229, 869, 10.1126/science.3895437 · DOI
  27. Goodwin, 1991, Molecular cloning and expression of the type 1 and type 2 murine receptors for tumor necrosis factor., Mol Cell Biol., 11, 3020, 10.1128/MCB.11.6.3020 · DOI
  28. Lewis, 1991, Cloning and expression of cDNAs for two distinct murine tumor necrosis factor receptors demonstrate one receptor is species specific., Proc Natl Acad Sci U S A., 88, 2830, 10.1073/pnas.88.7.2830 · DOI
  29. Tartaglia, 1991, The two different receptors for tumor necrosis factor mediate distinct cellular responses., Proc Natl Acad Sci U S A., 88, 9292, 10.1073/pnas.88.20.9292 · DOI
  30. Thoma, 1990, Identification of a 60 kd tumor necrosis factor (TNF) receptor as the major signal transducing component in TNF responses., J Exp Med., 172, 1019, 10.1084/jem.172.4.1019 · DOI
  31. Tartaglia, 1992, Two TNF receptors., Immunol Today., 13, 151, 10.1016/0167-5699(92)90116-O · DOI
  32. Heller, 1990, The p70 tumor necrosis factor receptor mediates cytotoxicity., Cell., 70, 47, 10.1016/0092-8674(92)90532-H · DOI
  33. Leist, 1995, Activation of the 55kDa TNF receptor is necessary and sufficient for TNF-induced liver failure, hepatocyte apoptosis, and nitrite release., J Immunol., 154, 1307, 10.4049/jimmunol.154.3.1307 · DOI
  34. Tartaglia, 1993, Tumor necrosis factor's cytotoxic activity is signaled by the p55 TNF receptor., Cell., 73, 213, 10.1016/0092-8674(93)90222-C · DOI
  35. Tartaglia, 1993, A novel domain within the 55 kd TNF receptor signals cell death., Cell., 74, 845, 10.1016/0092-8674(93)90464-2 · DOI
  36. Greenblatt, 1992, The type B receptor for tumor necrosis factor-α mediates DNA fragmentation in HL-60 and U937 cells and differentiation in HL-60 cells., Blood., 80, 1339, 10.1182/blood.V80.5.1339.1339 · DOI
  37. Pfeffer, 1993, Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection., Cell., 73, 457, 10.1016/0092-8674(93)90134-C · DOI · Paper page
  38. Albina, 1993, Nitric oxide-mediated apoptosis in murine peritoneal macrophages., J Immunol., 150, 5080, 10.4049/jimmunol.150.11.5080 · DOI
  39. Sarih, 1993, Nitric oxide synthase induces macrophage death by apoptosis., Biochem Biophys Res Commun., 191, 503, 10.1006/bbrc.1993.1246 · DOI
  40. Murray, 1997, Regulation of neutrophil apoptosis by tumor necrosis factor-alpha: requirement for TNFR55 and TNFR75 for induction of apoptosis in vitro., Blood., 90, 2772, 10.1182/blood.V90.7.2772 · DOI
  41. Torczynski, 1983, The complete nucleotide sequence of the rat 18S ribosomal RNA gene and comparison with the respective yeast and frog genes., Nucleic Acids Res., 11, 4879, 10.1093/nar/11.14.4879 · DOI
  42. Celada, 1984, Evidence for a gamma-interferon receptor that regulates macrophage tumoricidal activity., J Exp Med., 160, 55, 10.1084/jem.160.1.55 · DOI
  43. Zhang, 1995, Tumor necrosis factor (TNF) is a physiologic regulator of hematopoietic progenitor cells: increase of early hematopoietic progenitor cells in TNF receptor p55-deficient mice in vivo and potent inhibition of progenitor cell proliferation by TNF alpha in vitro., Blood., 86, 2930, 10.1182/blood.V86.8.2930.2930 · DOI
  44. Bruce, 1996, Altered neuronal and microglial responses to excitoxic and ischemic brain injury in mice lacking TNF receptors., Nat Med., 2, 788, 10.1038/nm0796-788 · DOI
  45. Diefenbach, 1998, Type 1 interferon (IFNalpha/beta) and type 2 nitric oxide synthase regulate the innate immune response to a protozoan parasite., Immunity., 8, 77, 10.1016/S1074-7613(00)80460-4 · DOI
  46. Hogquist, 1991, Interleukin 1 is processed and released during apoptosis., Proc Natl Acad Sci U S A., 88, 8485, 10.1073/pnas.88.19.8485 · DOI
  47. Chomczynski, 1987, Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction., Anal Biochem., 162, 156, 10.1016/0003-2697(87)90021-2 · DOI
  48. Perera, 1997, CD-14 dependent and CD-14-independent signaling pathways in murine macrophages from normal and CD-14 knockout mice stimulated with lipopolysaccharide or taxol., J Immunol., 158, 4422, 10.4049/jimmunol.158.9.4422 · DOI
  49. Schumann, 1990, Structure and function of lipopolysaccharide binding protein., Science., 249, 1429, 10.1126/science.2402637 · DOI
  50. Lakics, 1998, Lipopolysaccharide and ceramide use divergent signaling pathways to induce cell death in murine macrophages., J Immunol., 161, 2490, 10.4049/jimmunol.161.5.2490 · DOI
  51. Heneka, 1998, Induction of nitric oxide synthase and nitric oxide-mediated apoptosis in neuronal PC12 cells after stimulation with tumor necrosis factor-alpha/lipopolysaccharide., J Neurochem., 71, 88, 10.1046/j.1471-4159.1998.71010088.x · DOI
  52. Fehsel, 1995, Nitric oxide induces apoptosis in mouse thymocytes., J Immunol., 155, 2858, 10.4049/jimmunol.155.6.2858 · DOI
  53. Southam, 1995, Isothioureas: potent inhibitors of nitric oxide synthases with variable isoform selectivity., Br J Pharmacol., 114, 510, 10.1111/j.1476-5381.1995.tb13256.x · DOI
  54. Mathison, 1998, Participation of tumor necrosis factor in the mediation of Gram negative bacterial lipopolysaccharide-induced injury in rabbits., J Clin Invest., 81, 1925, 10.1172/JCI113540 · DOI
  55. Levine, 1997, p53, the cellular gatekeeper for growth and division., Cell., 88, 323, 10.1016/S0092-8674(00)81871-1 · DOI · Paper page
  56. Gottlieb, 1996, p53 in growth control and neoplasia., Biochem Biophys., 1287, 77
  57. Xiang, 1996, Bax-induced cell death may not require interleukin 1β-converting enzyme-like proteases., Proc Natl Acad Sci U S A., 93, 14559, 10.1073/pnas.93.25.14559 · DOI
  58. Messmer, 1996, Bcl-2 protects macrophages from nitric oxide-induced apoptosis., J Biol Chem., 271, 20192, 10.1074/jbc.271.33.20192 · DOI
  59. Wong, 1989, Manganous superoxide dismutase is essential for cellular resistance to cytotoxicity of tumor necrosis factor., Cell., 58, 923, 10.1016/0092-8674(89)90944-6 · DOI · Paper page
  60. Beg, 1996, An essential role for NF-κB in preventing TNF-α-induced cell death., Science., 274, 782, 10.1126/science.274.5288.782 · DOI · Paper page
  61. Van Antwerp, 1996, Suppression of TNF-α-induced apoptosis by NF-κB., Science., 274, 787, 10.1126/science.274.5288.787 · DOI
  62. Ayala, 1997, Factors responsible for peritoneal granulocyte apoptosis during sepsis., J Surg Res., 69, 67, 10.1006/jsre.1997.5027 · DOI
  63. Denecker, 1997, Differential role of calcium in tumor necrosis factor-mediated apoptosis and secretion of granulocyte-macrophage colony-stimulating factor in a T cell hybridoma., Cytokine., 9, 631, 10.1006/cyto.1997.0218 · DOI
  64. Akassoglou, 1998, Oligodendrocyte apoptosis and primary demyelination induced by local TNF/p55TNF receptor signaling in the central nervous system of transgenic mice: models for multiple sclerosis with primary oligodendrogliopathy., Am J Pathol., 153, 801, 10.1016/S0002-9440(10)65622-2 · DOI
  65. Nussler, 1991, l-arginine-dependent destruction of intrahepatic malaria parasites in response to tumor necrosis factor and/or interleukin 6 stimulation., Eur J Immunol., 21, 227, 10.1002/eji.1830210134 · DOI
  66. Nussler, 1993, Inflammation, immunoregulation, and inducible nitric oxide synthase., J Leukoc Biol., 54, 171, 10.1002/jlb.54.2.171 · DOI
  67. Hsu, 1996, TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways., Cell., 84, 299, 10.1016/S0092-8674(00)80984-8 · DOI
  68. Chinnaiyan, 1995, FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis., Cell., 81, 505, 10.1016/0092-8674(95)90071-3 · DOI · Paper page
  69. Boldin, 1996, Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/Apo-1- and TNF receptor-induced cell death., Cell., 85, 803, 10.1016/S0092-8674(00)81265-9 · DOI · Paper page
  70. Brune, 1997, Superoxide formation and macrophage resistance to nitric oxide-mediated apoptosis., J Biol Chem., 272, 7253, 10.1074/jbc.272.11.7253 · DOI
  71. Kitada, 1996, γ-radiation induces upregulation of Bax protein and apoptosis in radiosensitive cells in vivo., Oncogene., 12, 187
  72. Jurgensmeier, 1998, Bax directly induces release of cytochrome C from isolated mitochondria., Proc Natl Acad Sci U S A., 95, 4997, 10.1073/pnas.95.9.4997 · DOI
  73. Reed, 1997, Double identity for proteins of the Bcl-2 family., Nature., 387, 773, 10.1038/42867 · DOI
  74. Green, 1998, Mitochondria and apoptosis., Science., 281, 1309, 10.1126/science.281.5381.1309 · DOI

Cited by

Sorted by citations

See all 331

Metadata

Authors
Xaus, J., Comalada, M., Valledor, A. F., Lloberas, J., López-Soriano, F., Argilés, J. M., Bogdan, C., & Celada, A.
Affiliations
  • Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
  • From the Departament de Fisiologia (Biologia del Macròfag) and Fundació August Pi i Sunyer, Campus de Bellvitge; Departament de Bioquı́mica i Biologia Molecular, Facultat de Biologia Universitat de Barcelona, Barcelona, Spain; and the Institut für Klinische Mikrobiologie Immunologie und Hygiene, Universität Erlangen, Erlangen, Germany.
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2000-06-15
Volume
95
Issue
12
Pages
3823-3831
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood.v95.12.3823
OpenAlex
W1537320491
Cited by
331
References
4
Citations by year
2026: 9 · 2025: 13 · 2024: 15 · 2023: 19 · 2022: 14 · 2021: 14 · 2020: 14 · 2019: 14 · 2018: 23 · 2017: 11 · 2016: 15 · 2015: 17 · 2014: 14 · 2013: 13 · 2012: 14
FWCI
3.46
Type
journal article
Language
en
Open access
closed
Locations
  • Blood (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Universitat de Barcelona
  • Universidad de Cantabria
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Keywords
lipopolysaccharide, macrophage apoptosis, TNF-α, autocrine signaling, nitric oxide, inducible nitric oxide synthase, TNF receptor, p53, Bax, endotoxic shock, bone marrow-derived macrophages
MeSH terms
Animals, Bone Marrow Cells, Kinetics, Lipopolysaccharides, Macrophages, Mice, Inbred BALB C, Nitric Oxide, Penicillamine, Proto-Oncogene Proteins, Tumor Necrosis Factor-alpha, Antigens, CD, Genes, p53, Macrophage Colony-Stimulating Factor, Apoptosis, Receptors, Tumor Necrosis Factor, Mice, Knockout, Nitric Oxide Synthase, Proto-Oncogene Proteins c-bcl-2, Nitric Oxide Donors, S-Nitroso-N-Acetylpenicillamine, Receptors, Tumor Necrosis Factor, Type I, Receptors, Tumor Necrosis Factor, Type II, bcl-2-Associated X Protein, Mice, Nitric Oxide Synthase Type II, DNA Fragmentation

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review