engleski

Mechanisms of protective effects of interleukin-1 (IL-1) in acute hepatotoxicity

Introduction: It is known that Kupffer and other non-parenchymal liver cells are activated in hepatic injury, even if this is induced acutely by administration of high doses of hepatotoxic drugs. These cells secrete proinflammatory cytokines, prostaglandins (PG) and other products, which may contribute to pathogenic or repair processes. In these experiments we investigated the role of IL-1, which is known for its cytoprotective effect, in mice intoxicated with a lethal dose of acetaminophen (AAP). Materials and Methods: AAP (350 mg/kg) was given to mice by gastric lavage. The recombinant cytokines, PGs and antibodies to these agents were given to mice i.p. before or after AAP. The concentration of IL-1 and IL-6 in body fluids was determined in biossays with sensitive lines and concentration of PGs by RIA. Serum aminotransferase levels (AST and ALT) were determined by standard clinical laboratory methods. Results: IL-1a and IL-1b decreased mortality and serum aminotransferase levels when given to mice 2-20 hours before intoxication with AAP, and were without effect when given after AAP. Maximal effect was obtained with about 3 ng of IL-1a per mouse. Pretreatment with anti-IL-1 antibodies had an opposite effect. IL-1a stimulates IL-6 production in vivo in normal and AAP-intoxicated mice. It also stimulates the production of PGE2 and PGI2 and reduces the production of thromboxane A2 (TXA2) by liver fragments from AAP-intoxicated mice . Pretreatment of mice with polyclonal anti-PGE2 or monoclonal anti-IL-6 antibodies before IL-1a administration decreased its protective effect. Therefore, we investigated the direct protective effect of these two agents. 16-16-dimethyl-PGE 2 (a stable analogue of PGE2 ) had a strong protective effect if given to mice before or up to two hours after AAP. Similarly, recombinant mouse IL-6 (rmIL-6) had also significant protective effect, which was dose-dependent (400 to 10 000 U per mouse), but only if given before AAP. On the contrary, monoclonal antibodies to mouse rmIL-6, given to mice 3 hours before AAP, increased the mortality of mice and serum AST and ALT levels. IL-1a was also protective in mice with hepatoxicity induced with D-galactosamine and lipopolysaccharide. Presently, we are investigating the influence of IL-1 and PGE2 on synthesis of IL-1 receptor antagonist (IL-1Ra) and cyclic nucleotides (cAMP and cGMP), and effect of these agents on hepatotoxicity of AAP. Conclusion: Protective effect of IL-1 in mice with acute hepatotixicity induced with AAP is partly mediated by IL-6 and PGE2. These agents may further act by inducing the synthesis of IL-1Ra and/or cyclic nucleotides.

interleukin-1; interleukin-6; liver; hepatotoxicity; protection; PGE2; anti-IL-6 antibodies

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