Tumor Necrosis Factor Alpha Triggers Antiapoptotic Mechanisms in Rat Pancreatic Cells Through Pancreatitis-Associated Protein I Activation

Gastroenterology. 2000 Sep;119(3):816-28. doi: 10.1053/gast.2000.16491.


Background & aims: Tumor necrosis factor (TNF)-alpha contributes to the development of acute pancreatitis. Because TNF-alpha is involved in the control of apoptosis, we studied its interaction with the pancreatic apoptotic pathway.

Methods: Pancreatic acinar AR4-2J cells were used. Apoptosis was monitored by morphologic and biochemical criteria.

Results: TNF-alpha induced apoptosis in AR4-2J cells. Induction was strongly enhanced in cells treated with actinomycin D, suggesting that TNF-alpha activated concomitantly an antiapoptotic mechanism through newly synthesized proteins. This mechanism involved activation of nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein (MAP) kinases because their inhibition worsened TNF-alpha-induced apoptosis. The antiapoptotic pancreatitis-associated protein (PAP) I is a candidate for mediating TNF-alpha activity. Its expression is induced by TNF-alpha, and cells overexpressing PAP I show significantly less apoptosis on exposure to TNF-alpha. We examined whether TNF-alpha induction of PAP I expression was mediated by NF-kappaB or MAP kinases by using specific inhibitors of both pathways. Inhibition of NF-kappaB had no effect. However, inhibitors of MEK1 eliminated PAP I induction.

Conclusions: TNF-alpha induces concomitantly proapoptotic and antiapoptotic mechanisms in pancreatic AR4-2J cells. Antiapoptotic mechanisms are mediated by NF-kappaB and MAP kinases, and PAP I is one of the effectors of apoptosis inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute-Phase Proteins / metabolism
  • Acute-Phase Proteins / physiology*
  • Animals
  • Antigens, Neoplasm*
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Biomarkers, Tumor*
  • Cell Line
  • Dactinomycin / pharmacology
  • Drug Synergism
  • Lectins, C-Type*
  • MAP Kinase Kinase 1
  • Mitogen-Activated Protein Kinase Kinases / physiology
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • NF-kappa B / antagonists & inhibitors*
  • Pancreas / drug effects*
  • Pancreas / pathology
  • Pancreas / physiopathology*
  • Pancreatitis-Associated Proteins
  • Protein-Serine-Threonine Kinases / physiology
  • Rats
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / pharmacology
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Acute-Phase Proteins
  • Antigens, Neoplasm
  • Biomarkers, Tumor
  • Lectins, C-Type
  • NF-kappa B
  • Pancreatitis-Associated Proteins
  • REG3A protein, human
  • Recombinant Proteins
  • Reg3b protein, rat
  • Tumor Necrosis Factor-alpha
  • Dactinomycin
  • Protein-Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 1
  • Mitogen-Activated Protein Kinase Kinases