Increased expression of Smad6 deteriorates murine acute experimental pancreatitis in two models.
BACKGROUND
Smad6 is implicated in the inhibition of bone morphogenetic protein signalling. However, the function of Smad6 in the pancreas remains obscure.


METHODS
To elucidate the unknown function of Smad6, we developed transgenic mice selectively expressing Smad6 in pancreatic acinar cells using a plasmid construct coding rat elastase 1 enhancer/promoter.


RESULTS
Smad6 transgenic mice had no specific distinguishing phenotype such as body weight, pancreatic wet weight and concentrations of pancreatic protein. However, Smad6 transgenic mice reacted to hyperstimulation by caerulein injection or a diet containing 0.5% ethionine. Maximal amylase release stimulated by CCK-8 was significantly decreased in Smad6 transgenic mice acini, and trypsin activities in transgenic mice acini were significantly increased after stimulation of CCK-8. There was no difference in effect of CCK-8 stimulation on the subsequent increase in intracellular free Ca2+ concentration ([Ca2+](i)) between wild-type and transgenic mice acini. These findings suggest that reduced pancreatic enzyme secretion was caused by the disorder of its downstream signal transduction pathways in acinar cells. The amino acid sequence at the N-terminus of Smad6 was similar to that of synaptosome-associated protein (SNAP) 25 interacting protein, which plays an important role in regulating exocytosis of pancreatic enzymes in acinar cells. Pancreatic SNAP25 protein levels in transgenic mice were decreased after caerulein-induced pancreatitis.


CONCLUSIONS
These results suggest that elevated expression of Smad6 inhibits normal function of SNAP25-interacting protein and SNAP25, reduces amylase secretion in acinar cells, and increases the susceptibility of acinar cells to the onset of pancreatitis.
Nakamura
H
H
Third Department of Internal Medicine, University of Occupational and Environmental Health, Japan, School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku Kitakyushu 807-8555, Japan. hayaton@med.uoeh-u.ac.jp
Tashiro
M
M
Asaumi
H
H
Nomiyama
Y
Y
Kaku
M
M
Watanabe
S
S
Miyamoto
T
T
Otsuki
M
M
D000208:Acute Disease; D000595:Amino Acid Sequence; D000681:Amylases / Q000378:metabolism; D000818:Animals; D002108:Ceruletide; D004195:Disease Models, Animal; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D046790:Pancreas, Exocrine / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D016415:Sequence Alignment; D051905:Smad6 Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D015854:Up-Regulation
D012333:RNA, Messenger; D051905:Smad6 Protein; C497803:Smad6 protein, mouse; D050825:Synaptosomal-Associated Protein 25; D053773:Transforming Growth Factor beta1; D002108:Ceruletide; D000681:Amylases