Cytokine-mediated inflammatory hyperalgesia limited by interleukin-10.
1. The effect of interleukin-10 (IL-10) upon the hyperalgesic activities in rats of bradykinin, tumor necrosis factor alpha (TNF alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), interleukin-8 (IL-8), prostaglandin E2 (PGE2) and carrageenin were investigated in a model of mechanical hyperalgesia. 2. Hyperalgesic responses to bradykinin (1 micrograms) were inhibited in a dose-dependent manner by prior treatment with IL-10 (1-100 ng). 3. Hyperalgesic responses to TNF alpha (2.5 pg), IL-1 beta (0.5 pg) and IL-6 (1.0 ng) but not to IL-8 (0.1 ng) and PGE2 (50 ng and 100 ng) were inhibited by prior treatment with IL-10 (10 ng). 4. Hyperalgesic responses to carrageenin (100 micrograms) were inhibited by IL-10 (10 ng) when this cytokine was injected before but not after the carrageenin. 5. A monoclonal antibody to mouse IL-10 potentiated the hyperalgesic responses to carrageenin (10 micrograms) and TNF alpha (0.025 pg) but not that to IL-8 (0.01 ng). 6. In in vitro experiments in human peripheral blood mononuclear cells (MNCs), IL-10 (0.25-4.0 ng ml-1) inhibited in a dose-dependent manner PGE2 production by MNCs stimulated with IL-1 beta (1-64 ng ml-1) or endotoxin (lipopolysaccharide, LPS, 1 iu = 143 pg ml-1) but evoked only small increases in IL-1ra production. 7. These data suggest that IL-10 limits the inflammatory hyperalgesia evoked by carrageenin and bradykinin by two mechanisms: inhibition of cytokine production and inhibition of IL-1 beta evoked PGE2 production. Our data suggest that the latter effect is not mediated via IL-10 induced IL-Ira and may result from suppression by IL-10 of prostaglandin H synthase-2 (COX-2).
Poole
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S
Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Brazil.
Cunha
F Q
FQ
Selkirk
S
S
Lorenzetti
B B
BB
Ferreira
S H
SH
D000818:Animals; D001920:Bradykinin / Q000008:administration & dosage / Q000633:toxicity; D002351:Carrageenan / Q000008:administration & dosage / Q000633:toxicity; D015232:Dinoprostone / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005079:Excipients / Q000008:administration & dosage / Q000633:toxicity; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy*; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000008:administration & dosage / Q000633:toxicity; D016753:Interleukin-10 / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015850:Interleukin-6 / Q000008:administration & dosage / Q000633:toxicity; D016209:Interleukin-8 / Q000008:administration & dosage / Q000633:toxicity; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity; D051379:Mice; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D012795:Sialoglycoproteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000633:toxicity
D005079:Excipients; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D002351:Carrageenan; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D001920:Bradykinin