Connexins regulate cell functions in pancreatic stellate cells.
OBJECTIVE
Pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrosis associated with chronic pancreatitis and pancreatic cancer. Connexins (Cxs) allow direct intercellular communications as components of gap junction but also play important roles in the regulation of cell proliferation, cell differentiation, and tissue development. We here examined the expression of Cxs and Cx-mediated regulation of cell functions in PSCs.


METHODS
Human PSCs were isolated from patients undergoing operation for chronic pancreatitis or pancreatic cancer. The expression of Cxs was examined by reverse transcription polymerase chain reaction, Western blotting, and immunofluorescent staining. The roles of Cxs in PSC functions were examined by using carbenoxolone, a broad-spectrum Cx inhibitor, and small interfering RNA for Cx43.


RESULTS
Human activated PSCs expressed a variety of Cxs including Cx43 both in vitro and in vivo. Carbenoxolone inhibited platelet-derived growth factor-BB-induced proliferation and migration, and type I collagen expression in PSCs. In addition, carbenoxolone inhibited the activation of quiescent PSCs to a myofibroblastlike phenotype. Decreased Cx43 expression by small interfering RNA resulted in decreased proliferation and type I collagen expression.


CONCLUSIONS
Pancreatic stellate cells expressed a variety of Cxs. Connexins, especially Cx43, might regulate the cell functions and activation of PSCs.
Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan. amasamune@med.tohoku.ac.jp
Atsushi
A
Masamune
Noriaki
N
Suzuki
Kazuhiro
K
Kikuta
Hiroyuki
H
Ariga
Shintaro
S
Hayashi
Tetsuya
T
Takikawa
Kiyoshi
K
Kume
Shin
S
Hamada
Morihisa
M
Hirota
Atsushi
A
Kanno
Shinichi
S
Egawa
Michiaki
M
Unno
Tooru
T
Shimosegawa
D000818:Animals; D000077214:Becaplermin; D015153:Blotting, Western; D002229:Carbenoxolone / Q000494:pharmacology; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D018031:Connexin 43 / Q000378:metabolism; D017630:Connexins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis; D005455:Fluorescent Antibody Technique; D006801:Humans; D008297:Male; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D050500:Pancreatitis, Chronic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D024042:Collagen Type I; D018031:Connexin 43; D017630:Connexins; C500216:GJA1 protein, human; C580592:Gja1 protein, rat; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000077214:Becaplermin; D002229:Carbenoxolone