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

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-gamma(-/-) mice, suggesting that IL-15 mediated hypernociception via an IFN-gamma-, endothelin (ET)-, and prostaglandin-dependent pathway. Consistent with this finding, IFN-gamma 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-gamma 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-gamma-dependent manner. Prostaglandin E-2 (PGE(2)) production was induced by IL-15, IFN-gamma, or ET-1. We also found that hypernociception induced by ovalbumin (OVA) in OVA-immunized mice was significantly diminished by treatment with sIL-15R alpha (soluble IL-15 receptor a-chain), bosentan, BQ123, or indomethacin. Furthermore, OVA challenge induced the expression of PPET-1 mRNA in WT mice but not in IFN-gamma(-/-) mice. The PPET-1 mRNA expression was also inhibited by sIL-15Ra pretreatment. Therefore, our results demonstrate the sequential mechanical hypernociceptive effect of IL-15 -> IFN-gamma -> ET-1 -> PGE(2) and suggest that these molecules may be targets of therapeutic intervention in antigen-induced hypernociception.