CCK1 and CCK2 receptors are expressed on pancreatic stellate cells and induce collagen production.
The gastrointestinal hormone cholecystokinin (CCK) can induce acute pancreatitis in rodents through its action on acinar cells. Treatment with CCK, in combination with other agents, represents the most commonly used model to induce experimental chronic pancreatitis. Pancreatic stellate cells (PSC) are responsible for pancreatic fibrosis and therefore play a predominant role in the genesis of chronic pancreatitis. However, it is not known whether PSC express CCK receptors. Using real time PCR techniques, we demonstrate that CCK1 and CCK2 receptors are expressed on rat PSC. Interestingly both CCK and gastrin significantly induced type I collagen synthesis. Moreover, both inhibit proliferation. These effects are comparable with TGF-β-stimulated PSC. Furthermore, the natural agonists CCK and gastrin induce activation of pro-fibrogenic pathways Akt, ERK, and Src. Using specific CCK1 and CCK2 receptor (CCK2R) inhibitors, we found that Akt activation is mainly mediated by CCK2R. Akt activation by CCK and gastrin could be inhibited by the PI3K inhibitor wortmannin. Activation of ERK and the downstream target Elk-1 could be inhibited by the MEK inhibitor U0126. These data suggest that CCK and gastrin have direct activating effects on PSC, are able to induce collagen synthesis in these cells, and therefore appear to be important regulators of pancreatic fibrogenesis. Furthermore, similar to TGF-β, both CCK and gastrin inhibit proliferation in PSC.
Berna
Marc J
MJ
Universitätsklinikum Eppendorf, Medizinische Klinik I, 20246 Hamburg, Germany.
Seiz
Oliver
O
Nast
Jan Friso
JF
Benten
Daniel
D
Bläker
Michael
M
Koch
Johannes
J
Lohse
Ansgar W
AW
Pace
Andrea
A
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D003094:Collagen / Q000096:biosynthesis*; D024042:Collagen Type I / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005755:Gastrins / Q000378:metabolism; D005786:Gene Expression Regulation; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D010179:Pancreas / Q000378:metabolism*; D058954:Pancreatic Stellate Cells / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043887:Receptor, Cholecystokinin B / Q000096:biosynthesis*; D011949:Receptors, Cholecystokinin / Q000096:biosynthesis*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
D002070:Butadienes; D024042:Collagen Type I; D004791:Enzyme Inhibitors; D005755:Gastrins; D009570:Nitriles; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D016212:Transforming Growth Factor beta; C113580:U 0126; D003094:Collagen