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

Proceedings of the National Academy of Sciences of the United States of America - Tập 103 Số 25 - Trang 9721-9725 - 2006
Waldiceu A. Verri1, Thiago M. Cunha1, Carlos Amílcar Parada1, Xiao–Qing Wei2, Sérgio Henrique Ferreira1, Foo Y. Liew2, Fernando Q. Cunha1
1Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Avenida Bandeirantes 3900, 14049-900 Ribeirão Preto, São Paulo, Brazil
2Division of Immunology, Infection, and Inflammation, University of Glasgow, Glasgow G11 6NT, United Kingdom; and

Tóm tắt

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), ETAreceptor 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 ETBreceptor 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 → PGE2and suggest that these molecules may be targets of therapeutic intervention in antigen-induced hypernociception.

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Proceedings of the National Academy of Sciences of the United States of America

Tập 103 Số 25

9721-9725

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