Signal Transduction of Cerulein-Induced Cytokine Expression and Apoptosis in Pancreatic Acinar Cells

Abstract

The signaling pathways mediating cytokine production and apoptosis in pancreatic acinar cells have not been fully understood. We investigated the signal transduction of cerulein-induced cytokine IL-6 expression and apoptosis in pancreatic acinar AR42J cells. The wild-type cells and the cells transfected with mutant genes for signaling molecules (such as transcription factor NF-kappaB and AP-1) and ras, the upstream signal for mitogen-activated protein kinase (MAPK), were used. IL-6 level was determined in the medium by enzyme-linked immunosorbent assay (ELISA). Apoptosis was determined by viable cell counts and DNA fragmentation. Wild-type cells and transfected cells with control vector (pcDNA), IkappaB mutant gene (IkappaB mt), H-ras mutant gene (Ras N17), or c-jun dominant negative gene (TAM-67) were treated with cerulein for 24 hours. As a result, cerulein induced IL-6 expression time-dependently at 10(-8) M, and apoptosis dose-dependently at 24 h in the wild-type cells. Cerulein-induced IL-6 expression (at 10(-8) M) and apoptosis (at 10(-7) M) were inhibited in the transfected cells with mutant gene (IkappaB mt, Ras N17, TAM-67) as compared to pcDNA cells and the wild-type cells. In conclusion, cerulein induces cytokine expression and apoptotic cell death, which may be regulated by NF-kappaB, AP-1, and possibly MAPK in pancreatic acinar cells.