Autocrine role of endogenous interleukin-18 on inflammatory cytokine generation by human neutrophils

FASEB J. 2009 Jan;23(1):194-203. doi: 10.1096/fj.08-110213. Epub 2008 Sep 9.


Neutrophils are key players of innate immunity and influence inflammatory and immune reactions through the production of numerous cytokines. Interleukin-18 (IL-18) is known to stimulate several neutrophil responses, and recent evidence suggests that neutrophils might represent a source of IL-18. Here, we show that neutrophils constitutively produce both IL-18 and its antagonist, IL-18BP. Cell activation does not affect IL-18BP release but leads to an increased gene expression and secretion of IL-18, a process that depends on NF-kappaB activation. Moreover, endogenous IL-18 feeds back on the neutrophils to augment cytokine generation in lipopolysaccharide-treated cells. Accordingly, exogenous IL-18 can induce the gene expression and release of several inflammatory cytokines in neutrophils, including its own expression. We finally report that IL-18 activates the p38 MAPK, MEK/ERK, and PI3K/Akt pathways in neutrophils. The IKK cascade is also activated by IL-18, resulting in IkappaB-alpha degradation, NF-kappaB activation, and RelA phosphorylation. Accordingly, these pathways contribute to the generation of inflammatory cytokines in IL-18-stimulated neutrophils. By contrast, the phosphorylation and DNA-binding activity of various STAT proteins were not induced by IL-18. Collectively, our results unveil new interactions between IL-18 and neutrophils and further support a role for these cells in influencing both innate and adaptive immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation / physiology
  • Humans
  • I-kappa B Kinase / metabolism
  • Inflammation / metabolism*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Interleukin-18 / metabolism*
  • NF-kappa B / metabolism
  • Neutrophils / metabolism*
  • Oncogene Protein v-akt / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Signal Transduction
  • Time Factors
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Intercellular Signaling Peptides and Proteins
  • Interleukin-18
  • NF-kappa B
  • interleukin-18 binding protein
  • Phosphatidylinositol 3-Kinases
  • Oncogene Protein v-akt
  • I-kappa B Kinase
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases