Betacellulin protects from pancreatitis by activating stress-activated protein kinase.
OBJECTIVE
Acute pancreatitis (AP) is a serious, unpredictable clinical problem, the pathophysiology of which is poorly understood. Here, we evaluate whether betacellulin (BTC), a ligand of the epidermal growth factor receptor also able to activate the proapoptotic ERBB4 receptor, can protect against experimental AP.


METHODS
AP was induced in transgenic mice overexpressing BTC (BTC-tg), control mice, or control mice after administration of recombinant BTC. The severity of pancreatitis was assessed by measurements of serum amylase and lipase and histologic grading. The involvement of the stress-activated protein kinase (SAPK) was evaluated by treating BTC-tg mice with an SAPK inhibitor before induction of AP.


RESULTS
BTC-tg mice showed increased apoptosis and proliferation in the exocrine pancreas, indicating an increased cell turnover. There was a marked, epidermal growth factor receptor-independent decrease in pancreas weight. After induction of AP by cerulein injection, BTC-tg mice showed a significantly lower increase in serum amylase and lipase levels as well as less pronounced tissue necrosis, edema, and inflammation, as compared to nontransgenic littermates. This protective effect, also confirmed in the L-arginine AP model, was associated with increased phosphorylation of SAPK and abrogated after treatment of BTC-tg mice with a SAPK inhibitor. Finally, the protective effect of BTC against AP was confirmed by treating nontransgenic mice with recombinant BTC.


CONCLUSIONS
These findings indicate a potential application of the BTC/ERBB4 pathway for modulating the course of AP.
Dahlhoff
Maik
M
Institute of Molecular Animal Breeding and Biotechnology, Gene Center of the LMU Munich, Germany.
Algül
Hana
H
Siveke
Jens T
JT
Lesina
Marina
M
Wanke
Rüdiger
R
Wartmann
Thomas
T
Halangk
Walter
W
Schmid
Roland M
RM
Wolf
Eckhard
E
Schneider
Marlon R
MR
D000208:Acute Disease; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis; D066259:Betacellulin; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D010179:Pancreas / Q000473:pathology; D010195:Pancreatitis / Q000473:pathology / Q000517:prevention & control*; D066247:Receptor, ErbB-4
D000873:Anthracenes; D066259:Betacellulin; C587852:Btc protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C432165:pyrazolanthrone; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4; D048031:JNK Mitogen-Activated Protein Kinases