Abstract
Immune cells were identified in intact live mouse pancreatic lobules and their Ca2+ signals, evoked by various agents, characterized and compared with the simultaneously recorded Ca2+ signals in neighboring acinar and stellate cells. Immunochemistry in the live lobules indicated that the pancreatic immune cells most likely are macrophages. In the normal pancreas the density of these cells is very low, but induction of acute pancreatitis (AP), by a combination of ethanol and fatty acids, markedly increased the number of the immune cells. The principal agent eliciting Ca2+ signals in the pancreatic immune cells was ATP, but these cells also frequently produced Ca2+ signals in response to acetylcholine and to high concentrations of bradykinin. Pharmacological studies, using specific purinergic agonists and antagonists, indicated that the ATP-elicited Ca2+ signals were mediated by both P2Y1 and P2Y13 receptors. The pancreatic immune cells were not electrically excitable and the Ca2+ signals generated by ATP were primarily due to release of Ca2+ from internal stores followed by store-operated Ca2+ entry through Ca2+ release-activated Ca2+ channels. The ATP-induced intracellular Ca2+ liberation was dependent on both IP3 generation and IP3 receptors. We propose that the ATP-elicited Ca2+ signal generation in the pancreatic immune cells is likely to play an important role in the severe inflammatory response to the primary injury of the acinar cells that occurs in AP.
Highlights
IntroductionCytosolic Ca2+ signals in the acinar cells of the exocrine pancreas, evoked by acetylcholine (ACh) or cholecystokinin (CCK), control the physiologically important secretion of digestive enzymes and fluid
Cytosolic Ca2+ signals in the acinar cells of the exocrine pancreas, evoked by acetylcholine (ACh) or cholecystokinin (CCK), control the physiologically important secretion of digestive enzymes and fluid. 1 The mechanisms responsible for the primary intracellular Ca2+ release and the subsequent Ca2+ Release Activated Ca2+ (CRAC) entry of Ca2+ are well established. 1-4 the vast majority of Ca2+ signaling studies have been conducted on acutely isolated mouse acinar cells or small acinar cell clusters, the general validity of the results obtained has been confirmed by studies in more intact preparations as well as in experiments on human acinar cells. 1,5Whereas local repetitive Ca2+ rises regulate physiological secretion, global and sustained elevations of the cytosolic Ca2+ concentration ([Ca2+]i) initiate the disease acute pancreatitis (AP).[6]
X-cells identified as pancreatic immune cells In our previous study,[11] the unidentified X-cells displayed Ca2+ signals that were distinct from those observed in the well-known cells of the pancreatic lobules
Summary
Cytosolic Ca2+ signals in the acinar cells of the exocrine pancreas, evoked by acetylcholine (ACh) or cholecystokinin (CCK), control the physiologically important secretion of digestive enzymes and fluid. Whereas local repetitive Ca2+ rises regulate physiological secretion, global and sustained elevations of the cytosolic Ca2+ concentration ([Ca2+]i) initiate the disease acute pancreatitis (AP).[6] Such excessive Ca2+ signals can be elicited by a combination of ethanol and long chain fatty acids, bile acids or be drug-induced, for example by Asparaginase.[7] The sustained global elevation of [Ca2+]i is generally maintained by open CRAC channels,[2,6] but can occur via pressure-induced Piezo[1] activation of TRPV4 channels.[8]. There is, evidence indicating that bradykinin-elicited Ca2+ signals in the stellate cells
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