IL-15 mediates antigen-induced neutrophil migration by triggering IL-18 production

Eur J Immunol. 2007 Dec;37(12):3373-80. doi: 10.1002/eji.200737488.


We have investigated the mechanisms underlying IL-15-induced neutrophil migration into inflamed tissues. IL-15 induced neutrophil migration to the peritoneal cavity in mice in a time- and dose-dependent manner. The cell migration was not induced in IL-18-/-, MIP-1alpha (CCL3)-/-, TNFR1-/- or 5-LOX-/- mice but was normal in IFN-gamma-/- mice. IL-15-induced neutrophil migration was inhibited by anti-MIP-2 (CXCL2) antibody or MK886 (leukotriene synthesis inhibitor). IL-18-induced neutrophil migration was also dependent on TNFR1, MIP-1alpha, MIP-2 and leukotriene. Consistent with this observation, IL-15 induced IL-18 production, and IL-15 or IL-18 injection induced the production of MIP-2, MIP-1alpha, TNF-alpha and LTB4. In an antigen-specific inflammation model, ovalbumin (OVA)-induced neutrophil migration was completely inhibited by soluble IL-15Ralpha (sIL-15Ralpha) or anti-MIP-2 antibody. Furthermore, cell migration was absent in IL-18-/-, MIP-1alpha-/-, TNFR1-/-, or 5-LOX-/- mice. OVA challenge induced the release of MIP-2, MIP-1alpha, TNF-alpha and LTB4 in the peritoneal cavity in an IL-15- and IL-18-dependent manner. We also found that neutrophils from the peripheral blood and synovial fluid of patients with rheumatoid arthritis produced substantial amounts of IL-18 and LTB4 following activation by IL-15. Together, these results demonstrate that IL-15 plays an important role in antigen-induced neutrophil migration during inflammation, triggering a sequential OVA, IL-15, IL-18, MIP-2, MIP-1alpha, TNF-alpha, LTB4 and neutrophil migration signaling cascade.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonate 5-Lipoxygenase / deficiency
  • Arachidonate 5-Lipoxygenase / physiology
  • Arthritis, Rheumatoid / immunology
  • Chemokine CCL3 / deficiency
  • Chemokine CCL3 / physiology
  • Chemokine CXCL2 / physiology
  • Chemotaxis, Leukocyte / drug effects*
  • Humans
  • Injections, Intraperitoneal
  • Interleukin-15 / administration & dosage
  • Interleukin-15 / pharmacology
  • Interleukin-15 / physiology*
  • Interleukin-18 / biosynthesis
  • Interleukin-18 / deficiency
  • Interleukin-18 / physiology*
  • Leukotriene Antagonists / pharmacology
  • Leukotrienes / biosynthesis
  • Leukotrienes / physiology
  • Mice
  • Mice, Knockout
  • Neutrophils / cytology*
  • Ovalbumin / toxicity
  • Receptors, Tumor Necrosis Factor, Type I / deficiency
  • Receptors, Tumor Necrosis Factor, Type I / physiology
  • Recombinant Proteins / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Synovial Fluid / cytology
  • Tumor Necrosis Factor-alpha / biosynthesis


  • Ccl3 protein, mouse
  • Chemokine CCL3
  • Chemokine CXCL2
  • Cxcl2 protein, mouse
  • Interleukin-15
  • Interleukin-18
  • Leukotriene Antagonists
  • Leukotrienes
  • Receptors, Tumor Necrosis Factor, Type I
  • Recombinant Proteins
  • Tnfrsf1a protein, mouse
  • Tumor Necrosis Factor-alpha
  • Ovalbumin
  • Arachidonate 5-Lipoxygenase