Abstract
BackgroundAcute pancreatitis is potentially fatal but treatment options are limited as disease pathogenesis is poorly understood. IL-33, a novel IL-1 cytokine family member, plays a role in various inflammatory conditions but its role in acute pancreatitis is not well understood. Specifically, whether pancreatic acinar cells produce IL-33 when stressed or respond to IL-33 stimulation, and whether IL-33 exacerbates acute pancreatic inflammation is unknown.Methods/ResultsIn duct ligation-induced acute pancreatitis in mice and rats, we found that (a) IL-33 concentration was increased in the pancreas; (b) mast cells, which secrete and also respond to IL-33, showed degranulation in the pancreas and lung; (c) plasma histamine and pancreatic substance P concentrations were increased; and (d) pancreatic and pulmonary proinflammatory cytokine concentrations were increased. In isolated mouse pancreatic acinar cells, TNF-α stimulation increased IL-33 release while IL-33 stimulation increased proinflammatory cytokine release, both involving the ERK MAP kinase pathway; the flavonoid luteolin inhibited IL-33-stimulated IL-6 and CCL2/MCP-1 release. In mice without duct ligation, exogenous IL-33 administration induced pancreatic inflammation without mast cell degranulation or jejunal inflammation; pancreatic changes included multifocal edema and perivascular infiltration by neutrophils and some macrophages. ERK MAP kinase (but not p38 or JNK) and NF-kB subunit p65 were activated in the pancreas of mice receiving exogenous IL-33, and acinar cells isolated from the pancreas of these mice showed increased spontaneous cytokine release (IL-6, CXCL2/MIP-2α). Also, IL-33 activated ERK in human pancreatic tissue.SignificanceAs exogenous IL-33 does not induce jejunal inflammation in the same mice in which it induces pancreatic inflammation, we have discovered a potential role for an IL-33/acinar cell axis in the recruitment of neutrophils and macrophages and the exacerbation of acute pancreatic inflammation.ConclusionIL-33 is induced in acute pancreatitis, activates acinar cell proinflammatory pathways and exacerbates acute pancreatic inflammation.
Highlights
Acute pancreatitis is potentially fatal when it progresses to systemic inflammation and multi-organ failure.[1]
As exogenous IL-33 does not induce jejunal inflammation in the same mice in which it induces pancreatic inflammation, we have discovered a potential role for an IL-33/acinar cell axis in the recruitment of neutrophils and macrophages and the exacerbation of acute pancreatic inflammation
Samuel et al were the first to develop a fatal mouse model of distal common bile-pancreatic duct ligation-induced acute pancreatitis (PD), a model characterized by systemic inflammation and multiorgan dysfunction.[2]
Summary
Acute pancreatitis is potentially fatal when it progresses to systemic inflammation and multi-organ failure.[1] the mechanisms underlying the pathogenesis of acute pancreatitis are not well understood. As the elucidation of the important events in the early stages of disease progression in humans is not possible, we characterized a novel mouse model of pancreatic duct ligationinduced acute pancreatitis that is associated with systemic inflammation and substantial mortality.[2,3] The primary objective of the present study was to examine the potential role of the novel cytokine interleukin-33 (IL-33) in the pathogenesis of acute pancreatitis. We performed investigations to test the hypothesis that IL-33 exacerbates acute pancreatitis. Acute pancreatitis is potentially fatal but treatment options are limited as disease pathogenesis is poorly understood. Whether pancreatic acinar cells produce IL-33 when stressed or respond to IL-33 stimulation, and whether IL-33 exacerbates acute pancreatic inflammation is unknown
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