title: IL-15 mediates immune inflammatory hypernociception by triggering a sequential release of IFN-gamma, endothelin, and prostaglandin.
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-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 ET(B) 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-15Ralpha (soluble IL-15 receptor alpha-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-15Ralpha 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.
authors.affiliation: Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Avenida Bandeirantes 3900, 14049-900 Ribeirão Preto, São Paulo, Brazil.
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Parada
authors.forename: Xiao-qing
authors.initials: XQ
authors.lastname: Wei
authors.forename: Sérgio Henrique
authors.initials: SH
authors.lastname: Ferreira
authors.forename: Foo Y
authors.initials: FY
authors.lastname: Liew
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
mesh_terms: D000818:Animals; D016232:Endothelins / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D019409:Interleukin-15 / Q000494:pharmacology*; D051379:Mice; D010047:Ovalbumin / Q000494:pharmacology; D011453:Prostaglandins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D016232:Endothelins; D019409:Interleukin-15; D011453:Prostaglandins; D012333:RNA, Messenger; D007371:Interferon-gamma; D010047:Ovalbumin