IL-33 mediates antigen-induced cutaneous and articular hypernociception in mice

Verri, Jr., W. A., Guerrero, A. T. G., Fukada, S. Y., Valerio, D. A., Cunha, T. M., Xu, D., Ferreira, S. H., Liew, F. Y. and Cunha, F. Q. (2008) IL-33 mediates antigen-induced cutaneous and articular hypernociception in mice. Proceedings of the National Academy of Sciences of the United States of America, 105(7), pp. 2723-2728. (doi: 10.1073/pnas.0712116105)

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Publisher's URL: http://dx.doi.org/10.1073/pnas.0712116105

Abstract

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 (ET)A/ETB receptor antagonist], clazosentan (an ETA receptor antagonist), or indomethacin (a cyclooxygenase inhibitor). IL-33 induced hypernociception in IL-18−/− mice but not in TNFR1−/− or IFNγ−/− 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Liew, Prof Foo and Xu, Dr Damo and Fukada, Dr Sandra
Authors: Verri, Jr., W. A., Guerrero, A. T. G., Fukada, S. Y., Valerio, D. A., Cunha, T. M., Xu, D., Ferreira, S. H., Liew, F. Y., and Cunha, F. Q.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
ISSN:0027-8424
ISSN (Online):1091-6490
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
380241Toll-like receptors on T cellsFoo LiewMedical Research Council (MRC)G9818261Infection Immunity and Inflammation Medicine