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The novel cytokine interleukin-33 activates acinar cell proinflammatory pathways and induces acute pancreatic inflammation in mice
Journal article   Open access   Peer reviewed

The novel cytokine interleukin-33 activates acinar cell proinflammatory pathways and induces acute pancreatic inflammation in mice

Duraisamy Kempuraj, Erik C Twait, Deborah E Williard, Zuobiao Yuan, David K Meyerholz and Isaac Samuel
PloS one, Vol.8(2), pp.e56866-e56866
2013
DOI: 10.1371/journal.pone.0056866
PMCID: PMC3572073
PMID: 23418608
url
https://doi.org/10.1371/journal.pone.0056866View
Published (Version of record) Open Access

Abstract

Background Acute 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/Results In 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. Significance 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. Conclusion IL-33 is induced in acute pancreatitis, activates acinar cell proinflammatory pathways and exacerbates acute pancreatic inflammation.
 Immunohistochemistry Signal Transduction Humans Immunoblotting Male Interleukins - metabolism Interleukins - genetics Pancreatitis - genetics Inflammation Mediators - metabolism Mast Cells - metabolism Adult Female Lung - metabolism Interleukins - pharmacology Acinar Cells - metabolism Acute Disease Lung - pathology Cytokines - metabolism Interleukin-33 Mice, Inbred C57BL Cells, Cultured Pancreas - drug effects Pancreas - pathology Rats Pancreas - metabolism Reverse Transcriptase Polymerase Chain Reaction Mast Cells - drug effects Rats, Sprague-Dawley Animals Lung - drug effects Mice Pancreatitis - metabolism

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