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

doi:10.1073/pnas.0603286103

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

*Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Avenida Bandeirantes 3900, 14049-900 Ribeirão Preto, São Paulo, Brazil;
^†Division of Immunology, Infection, and Inflammation, University of Glasgow, Glasgow G11 6NT, United Kingdom; and
^‡Department of Dental Health and Biological Science, Cardiff University, Cardiff CF14 4XY, United Kingdom

Contributed by Sergio Henrique Ferreira, April 23, 2006

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 (ET_A)/endothelin receptor type B (ET_B) antagonist (bosentan), ET_A 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 ET_B 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.

Footnotes

^§To whom correspondence should be addressed. E-mail: shferrei{at}fmrp.usp.br
Author contributions: W.A.V., S.H.F., F.Q.C., F.Y.L., and T.M.C. designed research; W.A.V., T.M.C., and C.A.P. performed research; X.-q.W. and F.Y.L. contributed new reagents/analytic tools; W.A.V., F.Y.L., and F.Q.C. analyzed data; and W.A.V., T.M.C., F.Y.L., and F.Q.C. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations:

Abbreviations:

ET,

endothelin;

ETA,

ET receptor type A;

ETB,

ET receptor type B;

i.pl.,

intraplantar;

OVA,

ovalbumin;

PGE2,

prostaglandin E2;

RA,

rheumatoid arthritis;

sIL-15Rα,

soluble IL-15 receptor α-chain;;

TNFR1,

TNF receptor 1;

PPET-1,

preproET-1.