Co-operative effects of angiotensin II and caerulein in NFκB activation in pancreatic acinar cells in vitro

Angiotensin 11 is a vasoactive peptide that controls blood pressure and homeostasis. Emerging evidence shows that locally generated angiotensin II plays a crucial role in normal physiology, as well as pathophysiological conditions such as pancreatitis. We recently reported that angiotensin II activates pancreatic NF kappa B in obstructive pancreatitis. However, the specific cell type responsible for this activation remains unclear. In this study, we investigated whether pancreatic acinar cells respond to angiotensin II. These cells are the most abundant pancreatic cells and the most vulnerable to pancreatitis. Pancreatic acinar AR42J cells were used as an in vitro model of pancreatic inflammation. Our results demonstrated that treatment with caerulein, a cholecystokinin receptor agonist, induced hypersecretion and NF kappa B activation, as demonstrated by elevated amylase secretion and degradation of inhibitor of NF kappa B (I kappa B beta). Angiotensin II, either alone or in combination with caerulein, augmented I kappa B beta degradation. Pre-treatment with Iosartan, an antagonist of the angiotensin type I (AT(1)) receptor, abolished NF kappa B activation by angiotensin II and caerulein in a dose-dependent manner. Treatment with PD123319, a blocker of the angiotensin type II (AT(2)) receptor, enhanced the activation of NF kappa B by angiotensin II and caerulein. Preliminary data further demonstrated that angiotensin II could extend caerulein-induced ERK1/2 activation in acinar cells. These results indicated that inflammation triggered by hyperstimulation of pancreatic acinar cells is enhanced by angiotensin II, via the AT(1) receptor. In contrast, stimulation of the AT(2) receptor protects against caerulein-induced NF kappa B activation. The differential roles of the AT(1) and AT(2) receptors might be useful in developing potential therapies for pancreatic inflammation. (c) 2010 Elsevier B.V. All rights reserved.