Existence of autocrine loop between interleukin-6 and tranforming growth factor-β1 in activated rat pancreatic stellate cells

2006 ◽  
Vol 99 (1) ◽  
pp. 221-228 ◽  
Author(s):  
Hiroyoshi Aoki ◽  
Hirohide Ohnishi ◽  
Kouji Hama ◽  
Satoshi Shinozaki ◽  
Hiroto Kita ◽  
...  
Keyword(s):  
Growth Factor ◽  
Interleukin 6 ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Autocrine Loop

scholarly journals Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis

Gut ◽  
1999 ◽  
Vol 44 (4) ◽  
pp. 534-541 ◽  
Author(s):  
M V Apte ◽  
P S Haber ◽  
S J Darby ◽  
S C Rodgers ◽  
G W McCaughan ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Collagen Synthesis ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Oxidant Stress ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Cell Counts ◽  
Ecm Proteins

BACKGROUNDThe pathogenesis of pancreatic fibrosis is unknown. In the liver, stellate cells play a major role in fibrogenesis by synthesising increased amounts of collagen and other extracellular matrix (ECM) proteins when activated by profibrogenic mediators such as cytokines and oxidant stress.AIMSTo determine whether cultured rat pancreatic stellate cells produce collagen and other ECM proteins, and exhibit signs of activation when exposed to the cytokines platelet derived growth factor (PDGF) or transforming growth factor β (TGF-β).METHODSCultured pancreatic stellate cells were immunostained for the ECM proteins procollagen III, collagen I, laminin, and fibronectin using specific polyclonal antibodies. For cytokine studies, triplicate wells of cells were incubated with increasing concentrations of PDGF or TGF-β.RESULTSCultured pancreatic stellate cells stained strongly positive for all ECM proteins tested. Incubation of cells with 1, 5, and 10 ng/ml PDGF led to a significant dose related increase in cell counts as well as in the incorporation of3H-thymidine into DNA. Stellate cells exposed to 0.25, 0.5, and 1 ng/ml TGF-β showed a dose dependent increase in α smooth muscle actin expression and increased collagen synthesis. In addition, TGF-β increased the expression of PDGF receptors on stellate cells.CONCLUSIONSPancreatic stellate cells produce collagen and other extracellular matrix proteins, and respond to the cytokines PDGF and TGF-β by increased proliferation and increased collagen synthesis. These results suggest an important role for stellate cells in pancreatic fibrogenesis.

Hypoxia stimulates pancreatic stellate cells to induce fibrosis and angiogenesis in pancreatic cancer

2008 ◽  
Vol 295 (4) ◽  
pp. G709-G717 ◽  
Author(s):  
Atsushi Masamune ◽  
Kazuhiro Kikuta ◽  
Takashi Watanabe ◽  
Kennichi Satoh ◽  
Morihisa Hirota ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Growth Factor ◽  
Type I Collagen ◽  
Stellate Cells ◽  
Conditioned Media ◽  
Pancreatic Stellate Cells ◽  
Endothelial Cell Proliferation ◽  
Type I ◽  
Cell Functions ◽  
Pancreatic Cancer Cells

Pancreatic cancer is characterized by excessive desmoplastic reaction and by a hypoxic microenvironment within the solid tumor mass. Chronic pancreatitis is also characterized by fibrosis and hypoxia. Fibroblasts in the area of fibrosis in these pathological settings are now recognized as activated pancreatic stellate cells (PSCs). Recent studies have suggested that a hypoxic environment concomitantly exists not only in pancreatic cancer cells but also in surrounding PSCs. This study aimed to clarify whether hypoxia affected the cell functions in PSCs. Human PSCs were isolated and cultured under normoxia (21% O2) or hypoxia (1% O2). We examined the effects of hypoxia and conditioned media of hypoxia-treated PSCs on cell functions in PSCs and in human umbilical vein endothelial cells. Hypoxia induced migration, type I collagen expression, and vascular endothelial growth factor (VEGF) production in PSCs. Conditioned media of hypoxia-treated PSCs induced migration of PSCs, which was inhibited by anti-VEGF antibody but not by antibody against hepatocyte growth factor. Conditioned media of hypoxia-treated PSCs induced endothelial cell proliferation, migration, and angiogenesis in vitro and in vivo. PSCs expressed several angiogenesis-regulating molecules including VEGF receptors, angiopoietin-1, and Tie-2. In conclusion, hypoxia induced profibrogenic and proangiogenic responses in PSCs. In addition to their established profibrogenic roles, PSCs might play proangiogenic roles during the development of pancreatic fibrosis, where they are subjected to hypoxia.

Ethanol-mediated expression of connective tissue growth factor (CCN2) in mouse pancreatic stellate cells

2009 ◽  
Vol 27 (2) ◽  
pp. 91-99 ◽  
Author(s):  
Carmel Lawrencia ◽  
Alyssa Charrier ◽  
Guangcun Huang ◽  
David R. Brigstock
Keyword(s):  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Stellate Cells ◽  
Tissue Growth ◽  
Pancreatic Stellate Cells

scholarly journals HDGF supports anti-apoptosis and pro-fibrosis in pancreatic stellate cells of pancreatic cancer

2018 ◽  
Author(s):  
Yi-Ting Chen ◽  
Tso-Wen Wang ◽  
Tsung-Hao Chang ◽  
Teng-Po Hsu ◽  
Jhih-Ying Chi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Growth Factor ◽  
Cancer Cells ◽  
Transforming Growth Factor ◽  
Hypoxia Inducible Factor ◽  
Stellate Cells ◽  
Transforming Growth Factor Β1 ◽  
Pancreatic Stellate Cells ◽  
Pancreatic Cancer Cells ◽  
Tgf Β1

ABSTRACTPancreatic cancer is refractory and characterized by extensively surrounding- and intra-tumor fibrotic reactions that are contributed by activated pancreatic stellate cells (PSCs). Activation of PSCs plays a pivotal role for developing fibrotic reactions to affect themselves or pancreatic cancer cells (PCCs). In the current study, we demonstrated that hepatoma-derived growth factor (HDGF) was secreted from transforming growth factor-β1 (TGF-β1)-treated PSCs. We found that HDGF contributed to anti-apoptosis of PSCs and led to synthesis and depositions of extracellular matrix proteins for stabilizing PSCs/PCCs tumor foci. CCAAT/enhancer binding protein δ (CEBPD) responds to TGF-β1 through a reciprocal loop regulation and further activated hypoxia inducible factor-1α (HIF-1α) contributed to up-regulation ofHDGFgene. It agrees with the observation that severe stromal growth positively correlated with stromal HDGF and CEBPD in pancreatic cancer specimens. Collectively, the identification of TGF-β1-activated CEBPD/HIF-1α/HDGF axis provides new insights for the novel discoveries of HDGF in anti-apoptosis and pro-fibrosis of PSCs and outgrowth of pancreatic cancer cells.

Autocrine loop between TGF-β1 and IL-1β through Smad3- and ERK-dependent pathways in rat pancreatic stellate cells

2006 ◽  
Vol 290 (4) ◽  
pp. C1100-C1108 ◽  
Author(s):  
Hiroyoshi Aoki ◽  
Hirohide Ohnishi ◽  
Kouji Hama ◽  
Takako Ishijima ◽  
Yukihiro Satoh ◽  
...  
Keyword(s):  
Neutralizing Antibody ◽  
Stellate Cells ◽  
Dominant Negative ◽  
Pancreatic Fibrosis ◽  
Pancreatic Stellate Cells ◽  
Dependent Manner ◽  
Rt Pcr ◽  
Autocrine Loop ◽  
Dose Dependent ◽  
Tgf Β1

Pancreatic stellate cells (PSCs) are activated during pancreatitis and promote pancreatic fibrosis by producing and secreting ECMs such as collagen and fibronectin. IL-1β has been assumed to participate in pancreatic fibrosis by activating PSCs. Activated PSCs secrete various cytokines that regulate PSC function. In this study, we have examined IL-1β secretion from culture-activated PSCs as well as its regulatory mechanism. RT-PCR and ELISA have demonstrated that PSCs express IL-1β mRNA and secrete IL-1β peptide. Inhibition of TGF-β1 activity secreted from PSCs by TGF-β1-neutralizing antibody attenuated IL-1β secretion from PSCs. Exogenous TGF-β1 increased IL-1β expression and secretion by PSCs in a dose-dependent manner. Adenovirus-mediated expression of dominant-negative (dn)Smad2/3 expression reduced both basal and TGF-β1-stimulated IL-1β expression and secretion by PSCs. Coexpression of Smad3 with dnSmad2/3 restored IL-1β expression and secretion by PSCs, which were attenuated by dnSmad2/3 expression. In contrast, coexpression of Smad2 with dnSmad2/3 did not alter them. Furthermore, inhibition of IL-1β activity secreted from PSCs by IL-1β-neutralizing antibody attenuated TGF-β1 secretion from PSCs. Exogenous IL-1β enhanced TGF-β1 expression and secretion by PSCs. IL-1β activated ERK, and PD-98059, a MEK1 inhibitor, blocked IL-1β enhancement of TGF-β1 expression and secretion by PSCs. We propose that an autocrine loop exists between TGF-β1 and IL-1β in activated PSCs through Smad3- and ERK-dependent pathways.

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