title: 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.affiliation: Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.forename: Sérgio H
authors.initials: SH
authors.lastname: Ferreira
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Wei
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Leung
authors.forename: Alasdair
authors.initials: A
authors.lastname: Fraser
authors.forename: Iain B
authors.initials: IB
authors.lastname: McInnes
authors.forename: Foo Y
authors.initials: FY
authors.lastname: Liew
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency / Q000502:physiology; D001172:Arthritis, Rheumatoid / Q000276:immunology; D054405:Chemokine CCL3 / Q000172:deficiency / Q000502:physiology; D054426:Chemokine CXCL2 / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D006801:Humans; D007274:Injections, Intraperitoneal; D019409:Interleukin-15 / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology*; D020382:Interleukin-18 / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D020024:Leukotriene Antagonists / Q000494:pharmacology; D015289:Leukotrienes / Q000096:biosynthesis / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology*; D010047:Ovalbumin / Q000633:toxicity; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013582:Synovial Fluid / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: C496534:Ccl3 protein, mouse; D054405:Chemokine CCL3; D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D019409:Interleukin-15; D020382:Interleukin-18; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D010047:Ovalbumin; D001094:Arachidonate 5-Lipoxygenase