Cerulein pancreatitis: oxidative stress, inflammation, and apoptosis

Abstract

Cerulein pancreatitis is similar to human edematous pancreatitis, manifesting with dysregulation of digestive enzyme production and cytoplasmic vacuolization, the death of acinar cells, edema formation, and infiltration of inflammatory cells into the pancreas. Reactive oxygen species are involved in nuclear factor-kappaB activation, cytokine expression, apoptosis and pathogenesis of pancreatitis. There is recent evidence that cerulein activates NADPH oxidase, which is a major source of reactive oxygen species during inflammation and apoptosis in pancreatic acinar cells. In addition, the Janus kinase/signal transducer and activator of transcription pathway has been suggested as being involved in inflammatory signaling in the pancreas. This review discusses the involvement of oxidative stress in inflammation and apoptosis in pancreatic acinar cells stimulated with cerulein as an in vitro model of pancreatitis.

Keywords: Apoptosis; Cerulein; Inflammation; Pancreatitis.

Fig. 1

Proposed mechanism of how cerulein induces nuclear factor (NF)-κB activation and cytokine expression in pancreatic acinar cells. Cerulein binds the CCK receptor (R), which is a G-protein-coupled receptor. Ligand-receptor binding initiates transient Ca⁺⁺ oscillations by activating phospholipase C (PLC) and the induction of inositol 1,4,5-trisphosphate (IP₃)-dependent Ca⁺⁺ release from the endoplasmic reticulum (ER) in pancreatic acinar cells. Ca⁺⁺ can activate NADPH oxidase, which produces reactive oxygen species (ROS) that induce the activation of IκB kinase, which in turn phosphorylates IκB in the cytosol. IκB is an inhibitory subunit bound to NF-κB, a p65/p50 heterodimer in the cytosol. Phosphorylated IκB is ubiquitinated and degraded in a proteasome-dependent manner. NF-κB translocates to the nucleus and regulates cytokine expression. NF-κB is recycled after binding to IκB in the nucleus and transported to the cytosol. Therefore, ROS generated from cerulein appears to be the main contributor to cytokine production in acinar cells by directly activating the oxidant-sensitive transcription factor, NF-κB. ROS can disturb the integrity of the cytoskeleton and induce mitochondrial dysfunction in the cells. In the cytosol, the disulfide form of NF-κB is reduced to NF-κB by theoredoxin (TRX). PIP2, phosphatidylinositol 4, 5-bisphosphate; NF-κB subunit p50; 65, NF-κB subunit p65.