Global changes in interleukin-6-dependent gene expression patterns in mouse livers after partial hepatectomy

Liver regeneration following 70% partial hepatectomy leads to rapid activat ion of genes in the remnant liver. Interleukin-6 deficient (IL-6 -/-) mice have impaired liver regeneration and abnormalities in immediate early gene expression, In this study, the gene expression program in the IL-6 +/+ and -/- livers at 2 hours posthepatectomy was examined with a cDNA array repres enting 588 highly regulated mouse genes. Thirty-six percent of the 103 imme diate early genes were induced differently in IL-6 +/+ compared with IL-6 - /- livers, implying regulation by IL-6, IL-6 treatment of the IL-6 -/- mice in the absence of hepatectomy induced a much smaller set of genes in the l iver, suggesting that IL-6 cooperates with other hepatectomy-induced factor s to activate the large number of genes. Northern blot analyses were used t o verify gene expression data obtained from the arrays. The expression of u rokinase type plasminogen activator receptor (uPAR) and plasminogen activat or inhibitor-1 (PAI-1), critical components of the urokinase plasminogen ac tivator (uPA) system, was lower and delayed in IL-6 -/- livers. Despite the fact that active uPAR/uPA complex is critical for hepatocyte growth factor (HGF) activation, no differences were detected between the IL-6 +/+ and -/ - livers in HGF activation as measured by receptor phosphorylation. On the contrary, the mitogen-activated protein kinase (MAPK) pathway was activated in IL-6 +/+ livers early during regeneration but remarkably delayed in IL- 6 -/- livers. Defective liver regeneration may be explained by the large nu mber of gene activation pathways altered in IL-6 -/- livers and further sup ports the finding that IL-6 is necessary for normal liver regeneration.