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

Immunol Cell Biol. 2011 Aug;89(6):739-46. doi: 10.1038/icb.2010.168. Epub 2011 Jan 25.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Homeostasis / genetics
  • Homeostasis / immunology
  • Inflammation / immunology
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism
  • Interleukin-18 / genetics
  • Interleukin-18 / physiology*
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Lipopolysaccharides / toxicity*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Antigen, T-Cell, gamma-delta / immunology
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism
  • T-Lymphocytes / immunology

Substances

  • Interleukin-17
  • Interleukin-18
  • Lipopolysaccharides
  • Receptors, Antigen, T-Cell, gamma-delta
  • Interferon-gamma