Tumor necrosis factor alpha triggers antiapoptotic mechanisms in rat pancreatic cells through pancreatitis-associated protein I activation

Background & Aims: Tumor necrosis factor (TNF)-alpha contributes to the dev elopment of acute pancreatitis. Because TNF-alpha is involved in the contro l of apoptosis, we studied its interaction with the pancreatic apoptotic pa thway. Methods: Pancreatic acinar AR4-2J cells were used. Apoptosis was mon itored 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 a ntiapoptotic mechanism through newly synthesized proteins, This mechanism i nvolved activation of nuclear factor-kappa B (NF-kappa B) and mitogen-activ ated protein (MAP) kinases because their inhibition worsened TNF-alpha-indu ced 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 apoptosi s on exposure to TNF-alpha. We examined whether TNF-alpha induction of PAP I expression was mediated by NF-kappa B or MAP kinases by using specific in hibitors of both pathways, Inhibition of NF-kappa B had no effect. However, inhibitors of MEK1 eliminated PAP I induction. Conclusions: TNF-alpha indu ces concomitantly proapoptotic and antiapoptotic mechanisms in pancreatic A R4-2J cells. Antiapoptotic mechanisms are mediated by NF-kappa B and MAP ki nases, and PAP I is one of the effecters of apoptosis inhibition.