Die Aktivierung IL6/gp130 abhängiger Signalwege in Hepatozyten schützt die Leber vor Concanavalin A induzierter Hepatitis

Résumé fourni par la source

ME3738 is a new drug designed to treat patients with chronic liver diseases. A phase I trial was successfully performed in Japan. In earlier experiments we used the ConA model to study the mechanisms that confer ME3738-dependent protection. The ME3738-dependent effect is mediated via IL6. In this study we were interested to define the cell type involved in protection. We used tissue specific gp130 knockout animals. Expression of Cre recombinase is controlled by a hepatocyte-specific promotor element. After ME3738 stimulation IL6 levels increased in the serum of the knockout strain and the controls. In contrast to controls the increase in IL6 serum levels had no impact on STAT3 activation and acute phase gene expression in gp130-deleted animals. Further, gp130-deleted animals were pretreated with ME3738 before ConA injection. As ME3738 showed no protection in Alb-Cre/gp130 loxP animals, we could show that gp130-dependent pathways in hepatocyte are sufficient to confer protection against ConA induced liver failure. The relevance of these findings could be further confirmed as also IL6 pre-stimulation showed no protection from ConA induced liver injury. Next we determined the time course of IL6 and TNF protein in the serum of these animals. In controls IL6 expression increased after ConA injection and returned to normal after 48h. In ME3738 pretreated animals increased IL6 levels were found before ConA treatment, but rapidly decreased after stimulation. In contrast, in Alb-Cre/gp130loxP mice IL6 levels continuously increased after ConA injection and this time course could not be manipulated through ME3738 pretreatment. No significant impact on the TNF time course could be found using the different experimental conditions. Our results show that IL6 is involved in the resolution of inflammatory events in the progress of liver diseases.

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