engleski

The protective effect of interleukin 1alpha and IL-1beta on the acetaminophen induced liver toxicity relies on the early induction of their endogenous expression by acetaminophen itself

It is known that inflammatory cytokines influence the effect of hepatotoxic chemicals on liver. Previously we have shown that IL-1alpha and IL-6 have hepatoprotective effect if given to mice before administration of acetaminophen (APAP) and that this effect is partially mediated by PGE2. In these experiments we investigated the influence of IL-1beta in the same model, since we have been able to modulate its effect with specific antagonists (IL-1Ra and polyclonal anti- IL-1beta antibodies). APAP (300 mg/kg for survival and 200 mg/kg for determination of aminotransferases) or saline in controls were administered intragastrically to mice which were given phenobarbitone in drinking water for 7 days and fasted overnight IL-1beta 500 IU /mouse) or IL-1beta antibody (0.5 ml of rabbit to mouse IL-1, obtained by three consecutive injection of IL-1beta , first in complete FCA) were given i.p. 3 hours before APAP and IL-Ra (2.5 mg/mouse) half hour before APAP. The survival of mice was followed for 72 hours and concentration aminotransferases (AST and ALT) serum were determined 18-24 hours after administration of APAP. IL-1beta significantly increased the survival mice and decreased serum level of AST and ALT (p < 0.05). Just opposite effect had IL-1beta antibodies, but the effects were not significant. Similarly IL-1Ra, significantly increased serum concentration of AST and ALT (p < 0.05 or better) (the survival was not tested in this model). The finding that that IL-1Ra alone raised serum level of aminotranferases as well that potency IL-1beta antibodies alone showed the tendency to worse the manifestations of intoxication, promoted us to analyze the synthesis if IL-1 cytokines in non-treated animals intoxicated with AAP. RT-PCR analysis of the IL-1beta and IL-1alpha expression level in liver samples from APAP intoxicated mice has revealed that acetaminophen induces the expression of both cytokines already 1 hour after its intragastric administration. This expression was even higher at 6 hours following APAP administration and could be blocked by intravenous administration of aspirin at the dose which inhibits the activity of NF-kappa B transcription factor. Based on these results we hypothesized that organism intoxicated with APAP synthesizes its own IL-1 early on following APAP administration, which would represent a host defense reaction that could be helped by applying appropriate dose of exogenous cytokines.

interleukin 1beta and IL-1alpha; IL-1Ra; acetaminophen; liver toxicity

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