Tumor necrosis factor alpha triggers antiapoptotic mechanisms in rat pancreatic cells through pancreatitis-associated protein I activation.
OBJECTIVE
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.
Malka
D
D
Laboratoire de Recherche de Physiologie et Pathologie Digestives, INSERM Unité 315, Marseille, France.
Vasseur
S
S
Bödeker
H
H
Ortiz
E M
EM
Dusetti
N J
NJ
Verrando
P
P
Dagorn
J C
JC
Iovanna
J L
JL
D000209:Acute-Phase Proteins / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D000951:Antigens, Neoplasm; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D014408:Biomarkers, Tumor; D002460:Cell Line; D003609:Dactinomycin / Q000494:pharmacology; D004357:Drug Synergism; D037181:Lectins, C-Type; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010179:Pancreas / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*; D000073718:Pancreatitis-Associated Proteins; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D000209:Acute-Phase Proteins; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D037181:Lectins, C-Type; D016328:NF-kappa B; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; D011994:Recombinant Proteins; C000612144:Reg3b protein, rat; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases