Homeostatic defects in interleukin 18-deficient mice contribute to protection against the lethal effects of endotoxin

Daniel M. Andrews, Melvyn T. Chow, Yuting Ma, Claire Cotterell, Sally V. Watt, Desiree A. Anthony, Shizuo Akira, Yoichiro Iwakura, Joseph A. Trapani, Laurence Zitvogel, Mark J. Smyth

Research output: Contribution to journalArticle

12 Citations (Scopus)


Toll-like receptor-4-lipopolysaccharide (LPS)-mediated inflammation is used to delineate signals involved in cross-talk between antigen-presenting cells (APCs) and lymphocytes such as natural killer (NK) cells. Following APC stimulation and cytokine release, NK cells produce interferon (IFN)-γ. High levels of LPS induce endotoxicosis, a systemic inflammatory disease in which IFN-γ causes significant morbidity and mortality. Several studies have highlighted the role of interleukin (IL)-18, IL-1Β, IL-17A and IFN-γ in the development of endotoxicosis, but whether these cytokines interact with each other is yet to be determined. Our data demonstrate that IL-18 and IL-17A have important roles in NK cell IFN-γ production during endotoxicosis. Importantly, we provide the first evidence that IL-18 also has a role in IL-17A production by T-cell receptor (TCR)-cells. Furthermore, we demonstrate that IL-18-deficient mice have a defect in γ T-cell homeostasis and IL-1Β production, both of which can contribute to the development of disease through induction of IL-17A. These results reveal novel requirements for IL-18 in innate immune cell homeostasis and activation, demonstrating that the role of IL-18 in innate immunity occurs at a level other than activation.

Original languageEnglish
Pages (from-to)739-746
Number of pages8
JournalImmunology and Cell Biology
Issue number6
Publication statusPublished - Aug 2011
Externally publishedYes


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