Abstract
Pancreatic stellate cells (PSCs) are the main source of extracellular matrix proteins in pancreatic fibrosis, a pathological feature of chronic pancreatitis and pancreatic cancer. Interferon-gamma (IFN-gamma) is an antifibrotic cytokine, but how precisely it exerts its effects on PSCs is largely unknown. Here, we have focussed on the role of STAT1 as well as target genes of IFN-gamma signalling. Our data indicate that IFN-gamma regulates the expression of two autocrine mediators of PSC activation, connective tissue growth factor and endothelin-1, in a transforming growth factor-beta1-antagonistic manner. STAT1 overexpression under the control of a tetracycline-dependent promoter revealed a close correlation between STAT1 expression and activation, the biological effects of IFN-gamma (growth inhibition, induction of apoptosis), and target gene expression. Our data further support the hypothesis that IFN-gamma interferes with stellate cell activation in the pancreas and suggest activated STAT1 as an inductor of a quiescent PSC phenotype.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Cell Line
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Cell Proliferation / drug effects
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Connective Tissue Growth Factor
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Down-Regulation / drug effects*
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Endothelin-1 / genetics
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Endothelin-1 / metabolism
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Gene Expression / drug effects
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Humans
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Immediate-Early Proteins / genetics*
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Immediate-Early Proteins / metabolism
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Intercellular Signaling Peptides and Proteins / genetics*
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Intercellular Signaling Peptides and Proteins / metabolism
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Interferon-gamma / pharmacology*
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Pancreas / cytology*
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Pancreas / drug effects*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Rats
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STAT1 Transcription Factor / metabolism*
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins / genetics
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Suppressor of Cytokine Signaling Proteins / metabolism
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Tetracycline
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Transforming Growth Factor beta1 / pharmacology
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Up-Regulation / drug effects
Substances
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CCN2 protein, human
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CCN2 protein, rat
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Endothelin-1
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Immediate-Early Proteins
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Intercellular Signaling Peptides and Proteins
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RNA, Messenger
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STAT1 Transcription Factor
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Socs1 protein, rat
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Stat1 protein, rat
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Transforming Growth Factor beta1
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Connective Tissue Growth Factor
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Interferon-gamma
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Tetracycline