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 E(2) (PGE(2)) and carrageenin were investigated in a model of mechanical hyperalgesia. 2 Hyperalgesic responses to bradykinin (1 mu g) 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 PGE(2) (50 ng and 100 ng) were inhibited by prior treatment with IL-10 (10 ng). 4 Hyperalgesic responses to carrageenin (100 mu g) 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 mu g) 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 PGE(2) 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 PGE(2) production. Our data suggest that the latter effect is not mediated via IL-10 induced IL-1ra and may result from suppression by IL-10 of prostaglandin H synthase-2 (COX-2).