Epidermal Growth Factor Receptor Transactivation Mediates Tumor Necrosis Factor-induced Hepatocyte Replication

Gretchen M Argast,Jean S Campbell,John T Brooling,Nelson Fausto

doi:10.1074/jbc.m405703200

Abstract

Tumor necrosis factor (TNF) has multiple biological effects such as participating in inflammation, apoptosis, and cell proliferation, but the mechanisms of its effects on epithelial cell proliferation have not been examined in detail. At the early stages of liver regeneration, TNF functions as a priming agent for hepatocyte replication and increases the sensitivity of hepatocytes to growth factors such as transforming growth factor alpha (TGFalpha); however, the mechanisms by which TNF interacts with growth factors and enhances hepatocyte replication are not known. Using the AML-12 hepatocyte cell line, we show that TNF stimulates proliferation of these cells through transactivation of the epidermal growth factor receptor (EGFR). The transactivation mechanism involves the release of TGFalpha into the medium through activation of the metalloproteinase TNFalpha-converting enzyme (also known as ADAM 17). Binding of the ligand to EGFR initiates a mitogenic cascade through extracellular signal-regulated kinases 1 and 2 and the partial involvement of protein kinase B. TNF-induced release of TGFalpha and activation of EGFR signaling were inhibited by TNFalpha protease inhibitor-1, an agent that interferes with TNFalpha-converting enzyme activity. We suggest that TNF-induced transactivation of EGFR may provide an early signal for the entry of hepatocytes into the cell cycle and may integrate proliferative and survival pathways at the start of liver regeneration.

Highlights

Tumor necrosis factor (TNF)1 is a pleiotropic cytokine that plays a role in diverse cellular responses such as inflammation, apoptosis, and proliferation
Using the AML-12 hepatocyte cell line, we show that TNF stimulates proliferation of these cells through transactivation of the epidermal growth factor receptor (EGFR)
Induction of Cell Proliferation by Tumor Necrosis Factor—To study the effects of TNF on cell replication, AML-12 cells were maintained in serum-free medium for 24 h, a procedure that reduced DNA replication as determined by BrdUrd labeling to a basal level of less than 10%

Summary

Introduction

Tumor necrosis factor (TNF)1 is a pleiotropic cytokine that plays a role in diverse cellular responses such as inflammation, apoptosis, and proliferation. Using the AML-12 hepatocyte cell line, we show that TNF stimulates proliferation of these cells through transactivation of the epidermal growth factor receptor (EGFR). We examined the ability of TNF to stimulate DNA synthesis in cultures in which signaling from both the ligand (TGF␣) and its receptor (EGFR) was blocked.

Results

Conclusion