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

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

Full text not currently available from Enlighten.

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:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Liew, Prof Foo
Authors: Verri, W.A., Cunha, T.M., Parada, C.A., Wei, X.-Q., Ferreira, S.H., Liew, F.Y., and Cunha, F.Q.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
445191The role of the 1L-33 in the innate and adaptive immune responses in asthmaGrace MurphyMedical Research Council (MRC)G0601422III -IMMUNOLOGY