1 The effect of interleukin-10 (IL-10) upon the hyperalgesic activities in rats of bradykinin, tumor necrosis factor a (TNFa), interleukin-l, (IL-1fi), 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 Mg) were inhibited in a dose-dependent manner by prior treatment with IL-lO (1-100 ng).3 Hyperalgesic responses to TNFx (2.5 pg), IL-l1i (0.5 pg) and IL-6 (1.0 ng) but not to and PGE2 (50 ng and 100 ng) were inhibited by prior treatment with IL-10 (10 ng).4 Hyperalgesic responses to carrageenin (100 Mg) 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 Mg) and TNFa (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-) inhibited in a dose-dependent manner PGE2 production by MNCs stimulated with (1-64 ng ml-) or endotoxin (lipopolysaccharide, LPS, 1 iu = 143 pg ml-) but evoked only small increases in IL-Ira 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-lf 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).
1 The e ect of IL-4 on responses to intraplantar (i.pl.) carrageenin, bradykinin, TNFa, IL-1b, IL-8 and PGE 2 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 TNFa, but not responses to IL-1b, IL-8 and PGE 2 . 3 IL-4, 2 h before the injection of IL-1b, did not a ect the response to IL-1b, whereas IL-4, 12 or 12+2 h before the IL-1b, inhibited the hyperalgesia (730%, 774%, respectively). 4 In murine peritoneal macrophages, murine IL-4 for 2 h before stimulation with LPS, inhibited (740%) the production of IL-1b but not PGE 2 . Murine IL-4 (for 16 h before stimulation with LPS) inhibited LPS-stimulated PGE 2 but not IL-1b. 5 Anti-murine IL-4 antibodies potentiated responses to carrageenin, bradykinin and TNFa, but not IL-1b 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 in¯ammatory hyperalgesia. During the early phase of the in¯ammatory response the mode of action of the IL-4 appears to be inhibition of the production TNFa, IL-1b and IL-8. In the later phase of the response, in addition to inhibiting the production of pro-in¯ammatory cytokines, IL-4 also may inhibit the release of PGs.
It was previously shown that sustained fever can be induced in rats by central injection of endothelin-1 (ET-1). This peptide appears to participate in the mechanism(s) of LPS-induced fever, which is reduced by pretreatments with ET B receptor antagonists. In this study, we compared the effects of a nonselective cyclooxygenase (COX) inhibitor, indomethacin, with those of two selective COX-2 inhibitors, celecoxib and lumiracoxib, on ET-1-induced fever in rats. Fever induced in conscious animals by ET-1 (1 pmol icv) or LPS (5 g/kg iv) was prevented by pretreatments with celecoxib (5 and 10 mg/kg) or lumiracoxib (5 mg/kg) given by oral gavage 1 h before stimuli. Lower doses of celecoxib had partial (2.5 mg/kg) or no effect (1 mg/kg). Indomethacin (2 mg/kg ip) partially inhibited fever induced by LPS but had no effect on ET-1-induced fever. The levels of PGE2 and PGF2␣ in the cerebrospinal fluid (CSF) of pentobarbital sodium-anesthetized rats were significantly increased 3 h after the injection of LPS or ET-1. The latter increase was abolished by celecoxib at all tested doses and by indomethacin. In conclusion, selective COX-2 inhibitors were able to prevent ET-1-induced fever, indicating a role for COX-2 in this phenomenon. However, the fact that reduced CSF PG levels obtained with indomethacin and a low dose of celecoxib are not accompanied by changes in fever induced by ET-1, along with the lack of inhibitory effects of indomethacin on ET-1 fever, suggests that the latter might also involve COX-2-independent mechanisms.cyclooxygenase-2 inhibitors; indomethacin; prostaglandins; cerebrospinal fluid; lipopolysaccharide IT IS NOW WELL ESTABLISHED that the PGs represent the final mediators of fever induced by exogenous and endogenous pyrogens through an action on PG receptor-expressing neurons in the preoptic area (POA) of the anterior hypothalamus (33). In fact, PGE 2 induces fever when injected centrally (13,33,38), and its levels in the cerebrospinal fluid (CSF) and in the POA rise in parallel with the generation of fever caused by several stimuli (9,12,16,19,23,27,35,42). Moreover, the inhibition of PG synthesis by cyclooxygenase (COX) inhibitors attenuates fever in humans and experimental animals, whereas these drugs do not affect fever induced by the administration of PGs (4,7,12,13,37,39). PGF 2␣ also induces fever when injected centrally (13, 34), and its levels are increased in rat CSF in response to LPS (10).We have previously observed that endothelin-1 (ET-1), a member of the ET family of peptides (29), acts as a mediator of LPS-induced fever (15). In fact, intracerebroventricular (icv) pretreatment with the selective ET B receptor antagonist BQ-788 blunted fever induced by intravenous LPS or intracerebroventricular ET-1 (15). The rise in core temperature induced by intracerebroventricular ET-1 was accompanied by such thermoeffector response as cutaneous vasoconstriction, measured as a decrease in tail skin temperature (Fabricio, unpublished observation). The simultaneous occurrence of increased core temper...
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