Journal
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Volume 189, Issue 3, Pages 282-291Publisher
AMER THORACIC SOC
DOI: 10.1164/rccm.201308-1535OC
Keywords
IL-1; IL-18; anakinra; CASP11; sepsis
Categories
Funding
- European grant (FP6 ApopTrain) [MRTN-CT-035624]
- Ghent University
- Foundation against Cancer [F94]
- Flanders Institute for Biotechnology (VIB)
- Flemish Government [BOF09/01M00709]
- Belgian grants (Interuniversity Attraction Poles) [IAP 7/32]
- Flemish grants (Research Foundation Flanders) (Methusalem) [FWO G.0875.11, FWO G.0973.11, FWO G.0A45.12N, FWO G.0787.13N]
- European grant (FP7 EC RTD Integrated Project, Apo-Sys) [FP7-200767]
- European grant (Euregional PACT II)
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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-1 beta, 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-1 beta and IL-18 additively prevented LPS-induced mortality. The detrimental role of IL-1 beta 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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