Co-operative effects of angiotensin II and caerulein in NFκB activation in pancreatic acinar cells in vitro.
Angiotensin II 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 NFκB 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 NFκB activation, as demonstrated by elevated amylase secretion and degradation of inhibitor of NFκB (IκBβ). Angiotensin II, either alone or in combination with caerulein, augmented IκBβ degradation. Pre-treatment with losartan, an antagonist of the angiotensin type I (AT₁) receptor, abolished NFκB activation by angiotensin II and caerulein in a dose-dependent manner. Treatment with PD123319, a blocker of the angiotensin type II (AT₂) receptor, enhanced the activation of NFκB 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 AT₁ receptor. In contrast, stimulation of the AT₂ receptor protects against caerulein-induced NFκB activation. The differential roles of the AT₁ and AT₂ receptors might be useful in developing potential therapies for pancreatic inflammation.
Chan
Yuk Cheung
YC
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, China.
Leung
Po Sing
PS
D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002108:Ceruletide / Q000494:pharmacology; D004789:Enzyme Activation; D007093:Imidazoles; D019808:Losartan / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D046790:Pancreas, Exocrine / Q000187:drug effects / Q000378:metabolism*; D010195:Pancreatitis / Q000503:physiopathology; D011725:Pyridines; D051381:Rats; D044140:Receptor, Angiotensin, Type 1; D000516:alpha-Amylases / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D016328:NF-kappa B; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; C073402:PD 123319; D002108:Ceruletide; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000516:alpha-Amylases; D019808:Losartan