Suppression of NF-kappa B activation and cytokine production by N-acetylcysteine in pancreatic acinar cells

Reactive oxygen species (ROS), generated by infiltrating neutrophils, are c onsidered as an important regulator in the pathogenesis and development of pancreatitis. A hallmark of the inflammatory response is the induction of c ytokine gene expression, which may be regulated by oxidant-sensitive transc ription factor, nuclear factor-kappaB (NF-kappaB). Present study aims to in vestigate whether neutrophils primed by 4 beta -pharbol 12 beta -myristate 13 alpha -acetate (PMA) affect the productions of H2O2 and lipid peroxide ( LPO), NF-kappaB activation and cytokine production in pancreatic acinar cel ls, and whether these alterations were inhibited by N-acetylcysteine (NAC) and superoxide dismutase (SOD). Neutrophils generated ROS by stimulation wi th PMA, which was inhibited by NAC and SOD. In acinar cells, PMA-primed neu trophils increased the productions of H2O2, LPO, and cytokines both time an d dose dependently. PMA-primed neutrophils resulted in the activation of tw o species of NF-kappaB dimers (a p50/p65 heterodimer and a p50 homodimer) i n acinar cells. Both NAC and SOD inhibited neutrophil-induced, oxidant-medi ated alterations in acinar cells. In conclusion, ROS, generated by neutroph ils, activates NF-kappaB, resulting in upregulation of inflammatory cytokin es in acinar cells. Antioxidants such as NAC might be useful antiinflammato ry agents by inhibiting oxidant-mediated activation of NF-kappaB and decrea sing cytokine production. (C) 2000 Elsevier Science Inc.