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IL-15 mediates immune inflammatory hypernociception by triggering a sequential release of IFN-γ, endothelin, and prostaglandin

Verri Jr, W. A., Cunha, T. M., Parada, C. A., Wei, Xiao-Qing, Ferreira, S. H., Liew, F. Y. and Cunha, F. Q. 2006. IL-15 mediates immune inflammatory hypernociception by triggering a sequential release of IFN-γ, endothelin, and prostaglandin. Proceedings of the National Academy of Sciences 103 (25) , pp. 9721-9725. 10.1073/pnas.0603286103

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Abstract

IL-15 is closely associated with inflammatory diseases. IL-15 targeting is effective in treating experimental and clinical rheumatoid arthritis (RA). Because hyperalgesia accompanies RA, we investigated the ability of IL-15 to induced nociceptor sensitization (hypernociception). We report here that IL-15 induced time- and dose-dependent mechanical hypernociception in mice. IL-15-induced hypernociception was inhibited by treatment with a dual endothelin receptor type A (ETA)/endothelin receptor type B (ETB) antagonist (bosentan), ETA receptor antagonist (BQ123), or cyclooxygenase inhibitor (indomethacin). Moreover, IL-15 failed to induce hypernociception in IFN-γ−/− mice, suggesting that IL-15 mediated hypernociception via an IFN-γ-, endothelin (ET)-, and prostaglandin-dependent pathway. Consistent with this finding, IFN-γ and ET-1 induced dose- and time-dependent mechanical hypernociception that was inhibited by BQ123 or indomethacin but not BQ788 (an ETB receptor antagonist). IFN-γ induced the production of ET-1 and the expression of its mRNA precursor (preproET-1, PPET-1). Moreover, IL-15 also induced ET-1 production and PPET-1 mRNA expression in an IFN-γ-dependent manner. Prostaglandin E2 (PGE2) production was induced by IL-15, IFN-γ, or ET-1. We also found that hypernociception induced by ovalbumin (OVA) in OVA-immunized mice was significantly diminished by treatment with sIL-15Rα (soluble IL-15 receptor α-chain), bosentan, BQ123, or indomethacin. Furthermore, OVA challenge induced the expression of PPET-1 mRNA in WT mice but not in IFN-γ−/− mice. The PPET-1 mRNA expression was also inhibited by sIL-15Rα pretreatment. Therefore, our results demonstrate the sequential mechanical hypernociceptive effect of IL-15 → IFN-γ → ET-1 → PGE2 and suggest that these molecules may be targets of therapeutic intervention in antigen-induced hypernociception.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Dentistry
Uncontrolled Keywords: cytokines; hyperalgesia; inflammation; nociception; pain
Publisher: National Academy of Sciences
ISSN: 1091-6490
Last Modified: 04 Jun 2017 01:35
URI: http://orca-mwe.cf.ac.uk/id/eprint/669

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