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)-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)-δ cells. Furthermore, we demonstrate that IL-18-deficient mice have a defect in γδ 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.
Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia. daniel.andrews@petermac.org
Daniel M
DM
Andrews
Melvyn T
MT
Chow
Yuting
Y
Ma
Claire L
CL
Cotterell
Sally V
SV
Watt
Desiree A
DA
Anthony
Shizuo
S
Akira
Yoichiro
Y
Iwakura
Joseph A
JA
Trapani
Laurence
L
Zitvogel
Mark J
MJ
Smyth
D000818:Animals; D002478:Cells, Cultured; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D020382:Interleukin-18 / Q000235:genetics / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
D020381:Interleukin-17; D020382:Interleukin-18; D008070:Lipopolysaccharides; D016692:Receptors, Antigen, T-Cell, gamma-delta; D007371:Interferon-gamma