Evidence for IFN-gamma as a mediator of the lethality of endotoxin and tumor necrosis factor-alpha

Doherty, G M; Lange, J R; Langstein, H N; Alexander, H R; Buresh, C M; Norton, J A

doi:10.4049/jimmunol.149.5.1666

Cited by 300Immune Response and InflammationSepsis Diagnosis and TreatmentInflammation biomarkers and pathways

Evidence for IFN-gamma as a mediator of the lethality of endotoxin and tumor necrosis factor-alpha

Doherty, G M, Lange, J R, Langstein, H N, Alexander, H R, Buresh, C M, Norton, J A·1992·The Journal of Immunology

DOI 10.4049/jimmunol.149.5.1666

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Abstract

Current evidence indicates that endogenously produced peptide cytokines, most notably TNF-alpha and IL-1, mediate the lethality of experimental endotoxemia. Because circulating serum levels of IFN-gamma can be detected soon after TNF-alpha and IL-1 in response to endotoxin, we investigated the role of IFN-gamma in endotoxin and TNF-alpha lethality. Specific neutralizing antibodies to murine TNF-alpha (anti-TNF-alpha Ab) or murine IFN gamma (anti-IFN-gamma Ab) produced in our laboratory protected mice against the lethality of Escherichia coli endotoxin (LPS) administered 6 h later. Serum IFN-gamma levels 2 h after i.v. LPS were lower in mice treated with anti-TNF-alpha Ab compared to mice that received nonimmune IgG (median less than 2.5 vs 3.0 U/ml, P2 less than 0.05). In contrast, serum TNF-alpha levels 1 h after i.v. LPS peaked more than fourfold higher in mice treated with anti-IFN-gamma Ab compared to controls (median greater than 6400 vs 1405 pg/ml, p2 less than 0.05). Doses of TNF-alpha (300 micrograms/kg) and IFN-gamma (50,000 U) which were well tolerated when given individually were synergistically lethal in combination (0% lethality vs 100% lethality, P2 less than 0.001), and were associated with higher serum levels of IL-6 than with either cytokine alone. Anti-IFN-gamma Ab provided complete protection against exogenous human rTNF-alpha at the LD100 dose (1400 micrograms/kg, p2 less than 0.001), and in fact prevented lethality at doses four- to fivefold greater than the LD100 human rTNF-alpha (up to 6000 micrograms/kg). We conclude that IFN-gamma is synergistic with TNF-alpha, is essential for the lethality of LPS and TNF-alpha, and may have modulating effects on the negative control of serum levels of TNF-alpha after LPS in mice.

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The administration of recombinant cytokines (e.g., interleukin-1, interleukin-6, interleukin-12, interleukin-18, tumor necrosis factor, and interferon-γ) in animal models and for cancer treatment in humans induces severe toxic effects or lethality consistent with the central role of cytokines as mediators of hyperinflammation in cytokine storm.
“The administration of recombinant cytokines (e.g., interleukin-1, interleukin-6, interleukin-12, interleukin-18, tumor necrosis factor [TNF], and interferon-γ) in animal models and for cancer treatment in humans induces severe toxic effects or lethality consistent with the central role of cytokines as mediators of hyperinflammation in cytokine storm.”
From Cytokine storm (2020) · cites this paper as [27]

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Authors: Doherty, G. M., Lange, J. R., Langstein, H. N., Alexander, H. R., Buresh, C. M., & Norton, J. A.
Affiliations: National Institutes of Health (US)
ORCID: Doherty, G M
Langstein, H N
Norton, J A
Venue: The Journal of Immunology
Publisher: Oxford University Press (OUP)
Published: 1992-09-01
Volume: 149
Issue: 5
Pages: 1666-1670
ISSN: 0022-1767 (ISSN-L)
1550-6606
DOI: 10.4049/jimmunol.149.5.1666
OpenAlex: W1946578458
Cited by: 300
References: 0
Citations by year: 2026: 1 · 2025: 3 · 2024: 4 · 2023: 1 · 2022: 7 · 2021: 6 · 2020: 6 · 2019: 3 · 2018: 4 · 2016: 2 · 2015: 5 · 2014: 4 · 2013: 5 · 2012: 6
FWCI: 7.41
Type: journal article
Language: en
Open access: closed
Licence: academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations: The Journal of Immunology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
Keywords: interferon-gamma, TNF-α, endotoxemia, cytokine synergy, anti-TNF-alpha antibody, anti-IFN-gamma antibody, interleukin-6, serum cytokine levels, endotoxin tolerance, sepsis
MeSH terms: Animals, Antibodies, Endotoxins, Female, Interferon-gamma, Lipopolysaccharides, Mice, Inbred C3H, Rabbits, Tumor Necrosis Factor-alpha, Interleukin-6, Mice

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Evidence for IFN-gamma as a mediator of the lethality of endotoxin and tumor necrosis factor-alpha

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