The role of protein kinase B and mitogen-activated protein kinase in epidermal growth factor and tumor necrosis factor alpha-mediated rat hepatocyte survival and apoptosis

Perturbation of hepatocyte growth regulation is associated with a number of liver diseases such as fibrosis and cancer. These diseases are mediated by a network of growth factors and cytokines that regulate the induction of h epatocyte proliferation and apoptosis. In this study, we have investigated the role of signaling pathways activated by tumor necrosis factor alpha (TN F-alpha) and epidermal growth factor (EGF) in the regulation of apoptosis i nduced by transforming growth factor beta(1) (TGF-beta(1)), because this ph ysiological factor is believed to regulate spontaneous apoptosis in the liv er. We show that pretreatment with (10 ng/mL) EGF or (25 ng/mL) TNF-alpha c an suppress TGF-beta(1)-induced apoptosis by 73% and 50%, respectively, in isolated rat hepatocytes, However, suppression of TGF-beta(1)-induced apopt osis by EGF and TNF-alpha occurs via different protein kinase signaling pat hways. Using specific inhibitors, we show that suppression of apoptosis by EGF is dependent on activation of phosphoinositide 3-kinase (PI 3-kinase) a nd the extracellular signal regulated kinase (ERK) mitogen-activated protei n (MAP) kinase pathways, but not p38 MAP kinase. In contrast, suppression o f TGF-beta(1)-induced apoptosis by TNF-alpha does not require PI 3-kinase a nd protein kinase B (PKB or Akt)-mediated pathways, but is dependent on ERK and p38 MAP kinase activity. These data contribute to our understanding of the intracellular survival signals that play a role in normal liver homeos tasis and in diverse pathological conditions.