Inhibition of signal transducer and activator transcription factor 3 in rats with acute hepatic failure

In fulminant hepatic failure, survival is not possible without recovery of sufficient hepatocyte mass. Remarkably, only a few studies exist that provi de insight into the mechanisms that control proliferation of residual hepat ocytes after extensive hepatocyte loss. In this regard, the role of growth- regulatory factors, including pro-inflammatory cytokines such as interleuki n-6 (IL-6), is not well understood. In the present study we show that in ra ts with critically low (10%) hepatocyte mass, whether with or without ongoi ng liver cell necrosis, inhibition of liver regeneration is associated with early and sustained increase in blood IL-6 levels. Under these conditions, the signal transducer and activator of transcription (Stat3) DNA binding a ctivity was lowered at the time of G1/S cell-cycle transition. We further d emonstrate that the protein inhibitor of activated Stat3 (PIAS3) and the su ppressor of cytokine signaling (SOCS-1) were upregulated early after induct ion of liver failure (6-12 h), In vitro, IL-6 induced PIAS3 expression in H GF stimulated rat hepatocytes. These findings suggest that after massive he patocyte loss, an early and rapid rise in blood IL-6 levels may weaken the hepatic regenerative response through up-regulation of Stat3 inhibitors PIA S3 and SOCS-1. (C) 2000 Academic Press.