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Simultaneous Targeting of IL-1 and IL-18 Is Required for Protection against Inflammatory and Septic Shock
Open accessAbstract
Rationale: Sepsis is one of the leading causes of death around the world. The failure of clinical trials to treat sepsis demonstrates that the molecular mechanisms are multiple and are still insufficiently understood. Objectives: To clarify the long disputed hierarchical contribution of several central inflammatory mediators (IL-1β, IL-18, caspase [CASP] 7, CASP1, and CASP11) in septic shock and to explore their therapeutic potential. Methods: LPS- and tumor necrosis factor (TNF)-induced lethal shock, and cecal ligation and puncture (CLP) were performed in genetically or pharmacologically targeted mice. Body temperature and survival were monitored closely, and plasma was analyzed for several markers of cellular disintegration and inflammation. Measurements and Main Results: Interestingly, deficiency of both IL-1β and IL-18 additively prevented LPS-induced mortality. The detrimental role of IL-1β and IL-18 was confirmed in mice subjected to a lethal dose of TNF, or to a lethal CLP procedure. Although their upstream activator, CASP1, and its amplifier, CASP11, are considered potential therapeutic targets because of their crucial involvement in endotoxin-induced toxicity, CASP11- or CASP1/11-deficient mice were not, or hardly, protected against a lethal TNF or CLP challenge. In line with our results obtained in genetically deficient mice, only the combined neutralization of IL-1 and IL-18, using the IL-1 receptor antagonist anakinra and anti–IL-18 antibodies, conferred complete protection against endotoxin-induced lethality. Conclusions: Our data point toward the therapeutic potential of neutralizing IL-1 and IL-18 simultaneously in sepsis, rather than inhibiting the upstream inflammatory caspases.
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“(4) is etiologically involved in pathological conditions such as lethal septic shock (at least as induced by LPS) [610, 611].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [611]
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Metadata
- Authors
- Berghe, T. V., Demon, D., Bogaert, P., Vandendriessche, B., Goethals, A., Depuydt, B., Vuylsteke, M., Roelandt, R., Van Wonterghem, E., Vandenbroecke, J., Choi, S. M., Meyer, E., Krautwald, S., Declercq, W., Takahashi, N., Cauwels, A., & Vandenabeele, P.
- Affiliations
- VIB-UGent Center for Inflammation Research (BE)
- Ghent University (BE)
- Inflammation Research Center, VIB, Ghent, Belgium
- Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, and
- University Hospital Schleswig-Holstein (DE)
- ORCID
- Venue
- American Journal of Respiratory and Critical Care Medicine
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-02-01
- Volume
- 189
- Issue
- 3
- Pages
- 282-291
- ISSN
- 1073-449X (ISSN-L)
- 1535-4970
- OpenAlex
- W1971998620
- Cited by
- 173
- References
- 55
- Citations by year
- 2026: 3 · 2025: 13 · 2024: 16 · 2023: 7 · 2022: 16 · 2021: 16 · 2020: 14 · 2019: 20 · 2018: 17 · 2017: 10 · 2016: 13 · 2015: 16 · 2014: 10
- FWCI
- 12.33
- Type
- journal article
- Language
- en
- Open access
- green
- zenodo.org
- Locations
- American Journal of Respiratory and Critical Care Medicine (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, other-oa)
- Funders
- European Commission (200767)
- Fonds Wetenschappelijk Onderzoek (G.0875.11, FWO G.0973.11, G.0973.11, FWO G.0875.11)
- Universiteit Gent (01M00709)
- Vlaams Instituut voor Biotechnologie (BOF09/01M00709)
- Vlaamse regering (BOF09/01M00709)
- Fondation contre le Cancer
- Leibniz-Gemeinschaft
- Topics
- Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Sepsis Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- sepsis, septic shock, IL-1β, IL-18, caspase-1, caspase-11, caspase-7, TNF-α, cecal ligation and puncture, anakinra, inflammatory mediators
- MeSH terms
- Animals, Anti-Inflammatory Agents, Autoantibodies, Cecum, Drug Therapy, Combination, Lipopolysaccharides, Mice, Inbred C57BL, Shock, Septic, Tumor Necrosis Factor-alpha, Biomarkers, Mice, Knockout, Caspases, Caspase 1, Interleukin-18, Mice, Caspase 7, Caspases, Initiator, Interleukin-1beta, Interleukin 1 Receptor Antagonist Protein
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