Antigen-induced inflammatory mechanical hypernociception in mice is mediated by IL-18

Abstract

There is pre-clinical evidence that therapies targeting IL-18 might be beneficial in controlling arthropathies, which are accompanied by hypernociception (nociceptor sensitization). In the present study, we addressed the hypernociceptive role of IL-18 in a model of antigen-induced inflammation in mice and its mechanisms. In naïve mice, the intraplantar injection of IL-18 induced dose- and time-dependent mechanical hypernociception, which was inhibited in IFN-γ deficient (−/−) mice, and by the pre-treatment with bosentan (dual endothelin [ET] receptor antagonist), BQ123 (ET A receptor antagonist) or indomethacin (cyclooxygenase inhibitor). IL-18 hypernociception was unaffected in TNFR1 −/− mice or by the pre-treatment with sIL-15Rα (soluble form of IL-15 receptor), BQ788 (ET B receptor antagonist) or guanethidine (sympathetic blocker). The ovalbumin (OVA) challenge-induced mechanical hypernociception in immunized mice was inhibited by the pre-treatment with anti-IL-18 antibody or in IL-18 −/− mice. Furthermore, IL-18 induced significant IFN-γ production in the paw skin of naïve mice. The OVA challenge-induced IFN-γ and ET-1 productions were inhibited in IL-18 −/− immunized mice, as well as ET-1 production in IFN-γ −/− immunized mice. In addition, significant PGE 2 production was detected after IL-18 or ET-1 (via ET A receptors) injection in naïve mice. Taken together with previous data, these results suggest that IL-18 plays a significant role in antigen-induced inflammatory hypernociception via the production of IFN-γ, ET-1 and PGE 2. Thus, IL-18 and IL-18-downstream mediators demonstrated herein might constitute targets to inhibit antigen-induced inflammatory pain.