Effects of Mast-Cell Stabilization in Cerulein-Induced Acute Pancreatitis in Rats

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.

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“…Mast cell activation in various experimental models of acute pancreatitis is well established [26], [36], [37]. Yonetci et.…”

Section: Discussionmentioning

confidence: 99%

“…al. showed that the mast cell stabilizing agent ketotifen attenuates cerulein-induced acute pancreatitis in rats [37]. Zhao et.…”

Section: Discussionmentioning

confidence: 99%

The Novel Cytokine Interleukin-33 Activates Acinar Cell Proinflammatory Pathways and Induces Acute Pancreatic Inflammation in Mice

et al. 2013

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“…Sodium cromoglycate and ketotifen have been shown to stabilize mast cells and prevent the increment in density of mast cells. 15,34,35 Thus, it may be suggested that hyperhomocysteinemiainduced cardiac hypertrophy may be associated with increase in density of mast cells and their degranulation.…”

Section: Discussionmentioning

confidence: 99%

Effect of Mast Cell Stabilizers in Hyperhomocysteinemia-induced Cardiac Hypertrophy in Rats

Singh

Balakumar

2008

Journal of Cardiovascular Pharmacology

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“…We respectfully disagree with the title of the letter by Dr Braganza since at this stage we believe that the role of mast cells, or haematin-activated mast cells, in pancreatitis remains poorly understood and possibly controversial, based on few published studies. For example, the mast cell stabilising compounds ketotifen5 and cromolyn6 had a protective effect in cerulein- and taurodeoxycholate-induced pancreatitis, respectively. In contrast, studies using mast-cell-deficient animals ( Ws/Ws rats that have a deletion in the c-kit gene) have not supported a key role for mast cells in experimental closed duodenal loop-induced acute pancreatitis 7.…”

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confidence: 99%

Authors' response

Habtezion¹,

Omary²

2011

Gut

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Effects of Mast-Cell Stabilization in Cerulein-Induced Acute Pancreatitis in Rats

Cited by 25 publications

References 28 publications

The Novel Cytokine Interleukin-33 Activates Acinar Cell Proinflammatory Pathways and Induces Acute Pancreatic Inflammation in Mice

The Novel Cytokine Interleukin-33 Activates Acinar Cell Proinflammatory Pathways and Induces Acute Pancreatic Inflammation in Mice

Effect of Mast Cell Stabilizers in Hyperhomocysteinemia-induced Cardiac Hypertrophy in Rats

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