Regulation of c-Met expression in rats with acute hepatic failure

Background. Earlier we described a model of fulminant hepatic failure (FHF) in the rat where partial hepatectomy is combined with induction of right l iver lobe necrosis. In FHF rats, lack of hepatocyte proliferation was assoc iated with delayed expression of HGF and HGF receptor c-met. Since the c-me t promoter region has Sp1 binding sites, we decided to examine whether in F HF rats down-regulation of c-met is associated with decreased Spl function and whether changes in blood HGF, IL-6, and TGF beta1 levels might be respo nsible for these effects. Materials and methods. Induction of FHF, partial (2/3) hepatectomy (PH), an d sham hepatectomy (SH) was performed in adult Sprague-Dawley rats. The lev els of c-met mRNA and Spl DNA binding activity were studied in rat liver re mnants at different time points after surgery. Blood levels of HGF, IL-6, a nd TGF beta1 were also measured in these rats. Additionally, the effects of treatment with TGF-beta1, IL-6, or a combination of both on c-met expressi on and Sp1 DNA binding were studied in HGF-induced rat hepatocyte cultures. Results. Compared to SH rats, in PH rat livers c-met was up-regulated after 6 h and Sp1 DNA binding was at or only slightly lower than levels at all t ime points studied. In FHF rat livers, c-met expression was markedly reduce d after 2 and 6 h, moderate after 12 h, and undetectable after 24 h. At the same time, Sp1 DNA binding was detected at 2 h postinduction only. In FHF rats, blood levels of all three cytokines showed early and sustained elevat ion. In vitro, IL-6 had no effect on c-met expression, whereas TGF beta1 up regulated c-met. When used alone, none of the cytokines affected Spl DNA bi nding activity. In contrast, a combination of IL-6 and TGF beta1 down-regul ated c-met expression as well as Sp1 DNA binding activity. These effects we re dependent on the IL-6 concentration used. This study suggests that follo wing massive loss of hepatocyte mass in rats, early increase in blood IL-6 and TGF beta1 levels may weaken the expression of HGF receptor c-met in sur viving hepatocytes through suppression of Spl DNA binding. (C) 2001 Academi c Press.