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

Abstract

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.

• Authors: Waldiceu A Verri Jr, Thiago M Cunha, Sérgio H Ferreira, Xiaoqing Wei, Bernard P Leung, Alasdair Fraser, Iain B McInnes, Foo Y Liew, Fernando Q Cunha
• Journal: European journal of immunology (Eur J Immunol) Vol. 37 Issue 12 Pg. 3373-80 (Dec 2007) ISSN: 0014-2980 [Print] Germany
• PMID: 17979156 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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