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

Verri, W. A., Cunha, T. M., Ferreira, S. H., Wei, X., Leung, B. P., Fraser, A., McInnes, I. B. , Liew, F. Y. and Cunha, F. Q. (2007) IL-15 mediates antigen-induced neutrophil migration by triggering IL-18 production. European Journal of Immunology, 37(12), pp. 3373-3380. (doi: 10.1002/eji.200737488) (PMID:17979156)

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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<sup>–/–</sup>, MIP-1α (CCL3)<sup>–/–</sup>, TNFR1<sup>–/–</sup> or 5-LOX<sup>–/–</sup> mice but was normal in IFN-c<sup>–/–</sup> 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-1α, 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-1α, TNF-α and LTB<sub>4</sub>. In an antigen-specific inflammation model, ovalbumin (OVA)-induced neutrophil migration was completely inhibited by soluble IL-15Rα (sIL-15Rα) or anti-MIP-2 antibody. Furthermore, cell migration was absent in IL-18<sup>–/–</sup>, MIP-1α<sup>–/–</sup>, TNFR1<sup>–/–</sup>, or 5-LOX<sup>–/–</sup> mice. OVA challenge induced the release of MIP-2, MIP-1α, TNF-α and LTB<sub>4</sub> 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 LTB<sub>4</sub> 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-1α, TNF-α, LTB<sub>4</sub> and neutrophil migration signaling cascade.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Liew, Prof Foo and McInnes, Professor Iain and Fraser, Dr Alasdair and Leung, Dr Bernard
Authors: Verri, W. A., Cunha, T. M., Ferreira, S. H., Wei, X., Leung, B. P., Fraser, A., McInnes, I. B., Liew, F. Y., and Cunha, F. Q.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:European Journal of Immunology
Journal Abbr.:Eur. J. Immunol.
Publisher:Wiley-VCH Verlag Berlin
ISSN (Online):1521-4141
Published Online:02 November 2007

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
380241Toll-like receptors on T cellsFoo LiewMedical Research Council (MRC)G9818261/69296Infection Immunity and Inflammation Medicine