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

Background and Aims: Tumor necrosis factor (TNF)-α contributes to the development of acute pancreatitis. Because TNF-α 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-α induced apoptosis in AR4-2J cells. Induction was strongly enhanced in cells treated with actinomycin D, suggesting that TNF-α activated concomitantly an antiapoptotic mechanism through newly synthesized proteins. This mechanism involved activation of nuclear factor-κB (NF-κB) and mitogen-activated protein (MAP) kinases because their inhibition worsened TNF-α-induced apoptosis. The anti-apoptotic pancreatitis-associated protein (PAP) I is a candidate for mediating TNF-α activity. Its expression is induced by TNF-α, and cells overexpressing PAP I show significantly less apoptosis on exposure to TNF-α. We examined whether TNF-α induction of PAP I expression was mediated by NF-κB or MAP kinases by using specific inhibitors of both pathways. Inhibition of NF-κB had no effect. However, inhibitors of MEK1 eliminated PAP I induction. Conclusions: TNF-α induces concomitantly proapoptotic and antiapoptotic mechanisms in pancreatic AR4-2J cells. Antiapoptotic mechanisms are mediated by NF-κB and MAP kinases, and PAP I is one of the effectors of apoptosis inhibition.