engleski

Influence of interleukin 1 and interleukin 6 on acute liver injury induced by acetaminophen in mice

Overdose or chronic use of a high dose of acetaminophen (Paracetamol, APAP) is a major cause of acute liver failure in the western world. It is well established that interleukin 1 (IL-1) and interleukin 6 (IL-6) have cytoprotective effects in gastrointestinal tract and in several other tissues and cells. Thus, we wanted to investigate whether IL-1 and IL-6 are playing a role in host defense to toxic effect of APAP. CBAT6/T6 inbred mice of both sexes were intoxicated with single lethal (300 mg/kg) or high sublethal (200 mg/kg) dose of APAP, which was administered to animals by gastric lavage. The toxicity of APAP was determined by observing survival of mice during 48 hours, by measuring concentrations of aspartate-aminotransferase (AST) and alanine-aminotransferase (ALT) in plasma 20-24 hours (h) after APAP administration, and by liver histology. IL-1α was given to mice intraperitoneally (i.p.) in a dose (37, 111, 333, 1000, 3000, and 9000 units (U)/mouse) and time (1, 2, 6, 12, and 24 h before APAP) dependent manner. The best results were obtained with a dose of 1000 U/mouse and at 2 h before APAP, in which the IL-1α significantly reduced mortality of mice, elevation of plasma AST and ALT levels, and histopathological changes in liver in comparison to control animals. Recombinant mouse IL-6 (rmIL-6 ; 10000 U/mouse, i.p., 2 h before APAP) had shown mainly similar effect, while anti-mIL-6 monoclonal antibodies (α-mIL-6 ; 0.4 mg/mouse, i.p., 3 h before APAP) demonstrated opposite effect, although, without statistically significance. IL-1α, also, significantly increased production of IL-6 and prostaglandin E2 (PGE2) by liver fragments ex vivo. The results have shown that IL-1α exhibits a strong hepatoprotective effect, suggesting its protective action via increased synthesis of IL-6 and PGE2 in drug induced hepatotoxicity. Exogenously administered IL-6 and α-mIL-6, at least partially, support these observations. Presently, we are examining the role of PGE2 in APAP induced liver injury through, besides the above mentioned determinants of APAP toxicity, its effect on blood coagulation parameters, production of cyclic adenosine monophosphate (cAMP), synthesis of nitric oxyde (NO), and activation of nuclear factor kappa B (NF-κB).

liver injury; acetaminophen; IL-1alpha; IL-6; PGE2

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