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

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)-gamma. High levels of LPS induce endotoxicosis, a systemic inflammatory disease in which IFN-gamma causes significant morbidity and mortality. Several studies have highlighted the role of interleukin (IL)-18, IL-1 beta, IL-17A and IFN-gamma 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-gamma 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)-delta cells. Furthermore, we demonstrate that IL-18-deficient mice have a defect in gamma delta T-cell homeostasis and IL-1 beta 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. Immunology and Cell Biology (2011) 89, 739-746; doi:10.1038/icb.2010.168; published online 25 January 2011