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The role of prostaglandins and inflammatory cytokines in acute liver dammage by xenobiotics

Recently many data accumulated showing that inflammatory mediators can prevent or reduce the liver toxicity induced by xenobiotics. This is especially case for hepatotrophic cytokine interleukin 6 (IL-6), which is important factor for regeneration of liver and well of toxic liver damage induced by acetaminophen (APAP, Paracetamol), CCl4 and other hepatotoxicants (Galun and Axelrod 2002). In our experiments we have shown that exogenous prostaglandin E2 (PGE2) can reduce the toxicity of APAP if applied before or up to 3 hours after intoxication with (sub) lethal dose of APAP (Table 1). This effect of PGE2 can be completely blocked by specific anti- PGE2antibodies, which actually increased APAP toxicity in comparison to non-treated mice. Others (Guarner et a.l. 1988) have shown that PGI2 and pharmacology inhibition of thromboxane synthesis have hepatoprotective effect in the same model. In preliminary experiments, we recently confirmed these results, showing that the specific anti-thromboxane B2 antibodies reduce the toxic effect of APAP while anti-PGI2 antibodies increased it (unpublished results, Fig. 1). In addition, we have shown that antifungal agent ketoconazole, which has protective effect on APAP-induced toxicity, stimulates the synthesis of PGE2 and inhibits the synthesis of TxA2 in liver cells from intoxicated mice (Culo et al. 1995). Recombinant IL-1α and IL-1β , as well as IL-6, have hepatoprotective effect only if given if given before APAP (Renic et al 1993, Table 1). Protective effect of IL-1α can be cancelled by applying anti-PGE2 or anti-IL-6 antibodies, but only partially. By RT-PCR it was shown that application of APAP alone induced the expression of IL-1α and IL-6 in host liver cells, thus indicating that the synthesis of these cytokines is a part of host defense to toxic effect of APAP (Table 1). We have also shown that application of APAP greatly decreases the concentration of cAMP in their liver cells in comparison to untreated mice. Application of IL-1 before APAP reverses the level of cAMP toward normal levels ; this effect of IL-1 was inhibited by antagonist of cAMP synthesis – 2', 5'-dideoxyadenosine (DDA)(Table 1). Table 1. Main findings about effect of prostaglandins and inflammatory cytokines on APAP hepatotoxicity Agent Effect Given before (-) or after (+) APAP Reference PGI2 (stabile analog) Decrease of toxicity + 2 hours Guarner F et al. 1988. Heptology 8 ; 248-253 Thromboxane synthetase inhibitor (OKY 1581) Decrease of toxicity + 2 hours - “ - PGE2 (stabile analog) Decrease of toxicity + 2 up to 3 hours Renić M et al. 1992. Croat J Gastroenterol Hepatol 1:59-64, IL-1α Decrease of toxicity - 24 to – 0.5 hours Renić M et al. 1993. Cytokine 5:192-197 IL-1β Decrease of toxicity - 2 hours Aleksic J et al. 2006. Proceedings of 6th International Cytokine Conference, August 27-21, Vienna, Austria, ed. J. D. Schwarz-meier. Bologna: Medimond, G827C0071. IL-1Ra Increase of toxicity - 0, 5 hours - “ - APAP Induce expression of IL-1α and IL-6 in liver cells - - “ - IL-6 Decrease of toxicity - 2 hours Renić M et al. 1995. Period biol 97: 55 60. IL-1β and IL-6 Increase concentration cAMP in APAP-intoxicated mice Culo F, submitted Fig. 1. The influence of specific exogenously applied anti-prostanoid antibodies on survival mice intoxicated with lethal dose of APAP (300 mg/kg). Shown is mortality of in comparison to mortality in mice pretreated with saline before APAP (normalized to 100 % mortality). 12-21 mice per group ; * p  0.05. Therefore, we tested the effect the effect of stable agonist of cAMP (dibutyryl-cAMP, db-cAMP), DDA and specific inhibitor of phosphodiesterase IV (rolipram) on APAP-induced hepatotoxicity. Db-cAMP and rolipram had significant hepatoprotective effect (db-cAMP also if given up to 2 hours after APAP), as was shown by increased survival and decrement of serum aminotransferase levels, while DDA significantly increased serum aminotransferase levels (Figure 2). Since it is known that PGE2 and PGI2 increase the synthesis of cAMP in many cells, the increase of cAMP in liver cells might be common pathway for protective effect of these prostaglandins and inflammatory cytokines against APAP toxicity. Presently, we are investigating the intracellular pathways of protective effect of cAMP, particularly the role of PKA, NF-κ B and Stat3 protein in this process. Fig. 2. The concentration of serum aminotransferases in mice pretreated with cAMP analog (db-cAMP), inhibitor of adenylate cyclase (DDA) or inhibitor of phosphodiesterase IV (rolipram). Shown are the values of AST and ALT (U/L) as a percent of values obtained in group of mice given saline before APAP. Asterisks denote the significance to group treated saline: * p  0.05 ; ** p  0.01.

prostaglandin; acetaminophen; hepatotoxicity; db-cAMP; rolipram

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