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Am J Physiol Gastrointest Liver Physiol 278: G165-G172, 2000;
0193-1857/00 $5.00
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Vol. 278, Issue 1, G165-G172, January 2000

CEP-1347 inhibits caerulein-induced rat pancreatic JNK activation and ameliorates caerulein pancreatitis

Andreas C. C. Wagner1, Luca Mazzucchelli2, Matthew Miller3, Anna Marie Camoratto3, and Burkhard Göke1

Departments of 1 Gastroenterology and 2 Pathology, University of Bern, CH-3010 Bern, Switzerland; and 3 Cephalon Inc., West Chester, Pennsylvania 19380

Pancreatic caerulein-induced activation of c-Jun NH2-terminal kinase (JNK) has been reported, and JNK has been proposed as a mediator during induction of hyperstimulated pancreatitis. CEP-1347 has recently been described as a specific JNK inhibitor. We tested whether CEP-1347 inhibits caerulein-induced pancreatic JNK activation in isolated acini and in vivo. CEP-1347 dose dependently inhibited acinar caerulein-induced JNK activation with nearly complete inhibition at 2 µM but had no effect on digestive enzyme release. For in vivo studies, rats were pretreated with CEP-1347 before caerulein hyperstimulation. For assessment of JNK activation and histological alterations, animals were killed 30 min or 2 and 4 h after caerulein hyperstimulation, respectively. Pancreatic wet weight, serum enzyme levels, and pancreatic activity of p38 and extracellular signal-regulated kinase (ERK) were also determined. Caerulein hyperstimulation strongly activated JNK, p38, and ERK. CEP-1347 pretreatment dose dependently reduced caerulein-induced pancreatic JNK activation without p38 or ERK inhibition. JNK inhibition also reduced pancreatic edema formation and reduced histological severity of pancreatitis. Thus we show that CEP-1347 inhibits JNK activation in vivo and ameliorates caerulein-induced pancreatitis.

pancreatic stress response; dually phosphorylated kinases


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