Cytokine-mediated inflammatory hyperalgesia limited by interleukin-4.
1. The effect of IL-4 on responses to intraplantar (i.pl.) carrageenin, bradykinin, TNFalpha, IL-1beta, IL-8 and PGE2 was investigated in a model of mechanical hyperalgesia in rats. Also, the cellular source of the IL-4 was investigated. 2. IL-4, 30 min before the stimulus, inhibited responses to carrageenin, bradykinin, and TNFalpha, but not responses to IL-1beta, IL-8 and PGE2. 3. IL-4, 2 h before the injection of IL-1beta, did not affect the response to IL-1beta, whereas IL-4, 12 or 12+2 h before the IL-1beta, inhibited the hyperalgesia (-30%, -74%, respectively). 4. In murine peritoneal macrophages, murine IL-4 for 2 h before stimulation with LPS, inhibited (-40%) the production of IL-1beta but not PGE2. Murine IL-4 (for 16 h before stimulation with LPS) inhibited LPS-stimulated PGE2 but not IL-1beta. 5. Anti-murine IL-4 antibodies potentiated responses to carrageenin, bradykinin and TNFalpha, but not IL-1beta and IL-8, as well as responses to bradykinin in athymic rats but not in rats depleted of mast cells with compound 40/80. 6. These data suggest that IL-4 released by mast cells limits inflammatory hyperalgesia. During the early phase of the inflammatory response the mode of action of the IL-4 appears to be inhibition of the production TNFalpha, IL-1beta and IL-8. In the later phase of the response, in addition to inhibiting the production of pro-inflammatory cytokines, IL-4 also may inhibit the release of PGs.
Cunha
F Q
FQ
Department of Pharmacology, Faculty of Medicine of Ribeirão, Preto, University of São Paulo, Brazil.
Poole
S
S
Lorenzetti
B B
BB
Veiga
F H
FH
Ferreira
S H
SH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D001920:Bradykinin / Q000494:pharmacology; D002351:Carrageenan / Q000494:pharmacology; D002452:Cell Count; D016207:Cytokines / Q000494:pharmacology*; D003911:Dextrans / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology; D004357:Drug Synergism; D005079:Excipients / Q000494:pharmacology; D005528:Foot / Q000473:pathology; D006614:Hindlimb; D006930:Hyperalgesia / Q000139:chemically induced / Q000517:prevention & control*; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control*; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology; D015847:Interleukin-4 / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D016209:Interleukin-8 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000166:cytology; D051379:Mice; D051381:Rats; D011923:Rats, Nude; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D016207:Cytokines; D003911:Dextrans; D005079:Excipients; D007375:Interleukin-1; D016209:Interleukin-8; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D002351:Carrageenan; D015232:Dinoprostone; D001920:Bradykinin