IL-33/ST2 signalling contributes to carrageenin-induced innate inflammation and inflammatory pain: role of cytokines, endothelin-1 and prostaglandin E2.
OBJECTIVE
IL-33 signals through ST2 receptors and induces adaptive and innate inflammation. IL-33/ST2 is involved in adaptive inflammation-induced pain. Here, we have investigated the contribution of IL-33/ST2-triggered mechanisms to carrageenin-induced innate inflammation.


METHODS
Carrageenin- and IL-33-induced inflammatory responses were assessed in BALB/c- (WT) and ST2-deficient ((-/-) ) mice as follows: oedema (plethysmometer), myeloperoxidase activity (colorimetric assay), mechanical hyperalgesia (electronic version of von Frey filaments), cytokine levels (ELISA), PGE2 (RIA), mRNA expression (quantitative PCR), drug treatments targeting leukocyte recruitment (fucoidin), TNF-α (infliximab), CXCL1 (antibody to CXCL1), IL-1 (IL-1ra), endothelin ETA (clazosentan) and ETB (BQ788) receptors and COX (indomethacin).


RESULTS
Carrageenin injection increased ST2 and IL-33 mRNA expression and IL-33 production in paw skin samples. Carrageenin-induced paw oedema, hyperalgesia and myeloperoxidase activity were reduced in ST2(-/-) compared with WT mice, effects mimicked by IL-33 injection in the paw. Furthermore, IL-33-induced hyperalgesia was reduced by fucoidin suggesting a role for recruited leukocytes in its hyperalgesic effect. IL-33-induced hyperalgesia in naïve mice was reduced by treatments targeting TNF, CXCL1, IL-1, endothelin receptors and COX while carrageenin-induced ST2-dependent TNF-α, CXCL1, IL-1β, IL-10 and PGE2 production and preproET-1 mRNA expression. Combining IL-33 and carrageenin at doses that were ineffective as single treatment induced significant hyperalgesia, oedema, myeloperoxidase activity and cytokine production in a ST2-dependent manner.


CONCLUSIONS
IL-33/ST2 signalling triggers the production of inflammatory mediators contributing to carrageenin-induced inflammation. These data reinforces the importance of IL-33/ST2 signalling as a target in innate inflammation and inflammatory pain.
Departamento de Patologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Parana, Brazil.
A C
AC
Zarpelon
T M
TM
Cunha
J C
JC
Alves-Filho
L G
LG
Pinto
S H
SH
Ferreira
I B
IB
McInnes
D
D
Xu
F Y
FY
Liew
F Q
FQ
Cunha
W A
WA
Verri
D000818:Animals; D002351:Carrageenan / Q000633:toxicity; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000378:metabolism; D005260:Female; D007249:Inflammation / Q000276:immunology / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010146:Pain / Q000209:etiology / Q000276:immunology / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D016207:Cytokines; D019332:Endothelin-1; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D018836:Inflammation Mediators; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D002351:Carrageenan; D015232:Dinoprostone