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 (ET)(A)/ET(B) receptor antagonist], clazosentan (an ET(A) receptor antagonist), or indomethacin (a cyclooxygenase inhibitor). IL-33 induced hypernociception in IL-18(-/-) mice but not in TNFR1(-/-) or IFNgamma(-/-) 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 IFNgamma 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 --> TNFalpha --> IL-1beta --> IFNgamma --> ET-1 --> PGE(2) 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.
Verri
Waldiceu A
WA
Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes, 3900, 14049-900-Ribeirão Preto, São Paulo, Brazil.
Guerrero
Ana T G
AT
Fukada
Sandra Y
SY
Valerio
Daniel A
DA
Cunha
Thiago M
TM
Xu
Damo
D
Ferreira
Sérgio H
SH
Liew
Foo Y
FY
Cunha
Fernando Q
FQ
D016604:Aflatoxin B1 / Q000494:pharmacology; D000818:Animals; D000941:Antigens / Q000276:immunology*; D015232:Dinoprostone / Q000096:biosynthesis; D019332:Endothelin-1 / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007378:Interleukins / Q000276:immunology*; D008297:Male; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D010146:Pain / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D012709:Serum Albumin / Q000494:pharmacology; D012867:Skin / Q000098:blood supply / Q000187:drug effects / Q000276:immunology* / Q000473:pathology
D000941:Antigens; D019332:Endothelin-1; D007378:Interleukins; D012333:RNA, Messenger; D012709:Serum Albumin; C052669:aflatoxin B1-bovine serum albumin; D016604:Aflatoxin B1; D015232:Dinoprostone