IL-33 Mediates Antigen-Induced Cutaneous and Articular Hypernociception in Mice

IL-33, a new member of the IL-1 family, signals through its receptor ST2 and induces T helper 2 (Th2) cytokine synthesis and mediates inflammatory response. We have investigated the role of IL-33 in antigen-induced hypernociception. Recombinant IL-33 induced cutaneous and articular mechanical hypernociception in a time- and dose-dependent manner. The hypernociception was inhibited by soluble (s) ST2 (a decoy receptor of IL-33), IL-1 receptor antagonist (IL-1ra), bosentan [a dual endothelin $({\rm ET})_{{\rm A}}/{\rm ET}_{{\rm B}}$ receptor antagonist], clazosentan (an ${\rm ET}_{{\rm A}}$ receptor antagonist), or indomethacin (a cyclooxygenase inhibitor). IL-33 induced hypernociception in ${\rm IL}\text{-}18^{-/-}$ mice but not in ${\rm TNFR}1^{-/-}$ or ${\rm IFN}\gamma ^{-/-}$ mice. The IL-33-induced hypernociception was not affected by blocking IL-15 or sympathetic amines (guanethidine). Furthermore, methylated BSA (mBSA)-induced cutaneous and articular mechanical hypernociception depended on TNFR1 and IFNγ and was blocked by sST2, IL-1ra, bosentan, clazosentan, and indomethacin. mBSA also induced significant IL-33 and ST2 mRNA expression. Importantly, we showed that mBSA induced hypernociception via the IL-33 → TNFα → IL-1β → IFNγ → ET-1 → PGE₂ signaling cascade. These results therefore demonstrate that IL-33 is a key mediator of immune inflammatory hypernociception normally associated with a Th1 type of response, revealing a hitherto unrecognized function of IL-33 in a key immune pharmacological pathway that may be amenable to therapeutic intervention.