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Am J Physiol Cell Physiol (December 21, 2005). doi:10.1152/ajpcell.00465.2005
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Submitted on September 19, 2005
Accepted on November 16, 2005

Autocrine Loop between Transforming Growth Factor-{beta} 1and Interleukin-1{beta} through Smad3- and ERK-dependent Pathways in Rat Pancreatic Stellate Cells

Hiroyoshi Aoki1, Hirohide Ohnishi1*, Kouji Hama1, Takako Ishijima1, Yukihiro Satoh1, Kazunobu Hanatsuka1, Akira Ohashi1, Shinichi Wada1, Tomohiko Miyata1, Hiroto Kita1, Hironori Yamamoto1, Hiroyuki Osawa1, Kiichi Sato1, Kiichi Tamada1, Hiroshi Yasuda2, Hirosato Mashima3, and Kentaro Sugano1

1 Department of Gastroenterology, Jichi Medical School, Kawachi, Tochigi, Japan
2 Dvision of Gastroenterology, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan
3 Department of Gastroenterology, University of Tokyo, Bunkyo, Tokyo, Japan

* To whom correspondence should be addressed. E-mail: hohnishi{at}jichi.ac.jp.

Pancreatic stellate cells are activated during pancreatitis and promote pancreatic fibrosis by producing and secreting extracellular matrix such as collagen and fibronectin. Interleukin-1{beta} has been assumed to participate in pancreatic fibrosis by activating pancreatic stellate cells (PSCs). Activated PSCs secrete various cytokines that regulate PSC functions. In this study, we examined IL-1{beta} secretion from culture-activated PSCs and its regulatory mechanism. RT-PCR and ELISA demonstrated that PSCs express IL-1{beta} mRNA and secrete IL-1{beta} peptide. Inhibition of TGF-{beta}1 activity secreted from PSCs by TGF-{beta}1 neutralizing antibody attenuated IL-1{beta} secretion from PSCs. Exogenous TGF-{beta}1 increased IL-1{beta} expression and secretion by PSCs in a dose-dependent manner. Adenovirus-mediated expression of dominant-negative Smad 2/3 expression reduced both basal and TGF-{beta}1 stimulated IL-1{beta} expression and secretion by PSCs. Co-expression of Smad 3 with dominant-negative Smad 2/3 restored IL-1{beta} expression and secretion by PSCs, which were attenuated by dominant-negative Smad 2/3 expression. In contrast, co-expression of Smad 2 with dominant-negative Smad 2/3 did not alter them. Furthermore, inhibition of IL-1{beta} activity secreted from PSCs by IL-1{beta} neutralizing antibody attenuated TGF-{beta}1 secretion from PSCs. Exogenous IL-1{beta} enhanced TGF-{beta}1 expression and secretion by PSCs. IL-1{beta} activated ERK, and PD98059, a MEK1 inhibitor, blocked IL-1{beta} enhancement of TGF-{beta}1 expression and secretion by PSCs. We propose that there exists an autocrine loop between TGF-{beta}1 and IL-1{beta} in activated PSCs through Smad 3 and ERK dependent pathways.




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