Inhibitory effects of interferon-gamma on activation of rat pancreatic stellate cells are mediated by STAT1 and involve down-regulation of CTGF expression.
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.
Fitzner
Brit
B
Department of Medicine, Division of Gastroenterology, University of Rostock, E-Heydemann-Str 6, 18057, 18057 Rostock, Germany.
Brock
Peter
P
Nechutova
Hana
H
Glass
Anne
A
Karopka
Thomas
T
Koczan
Dirk
D
Thiesen
Hans-Jürgen
HJ
Sparmann
Gisela
G
Emmrich
Jörg
J
Liebe
Stefan
S
Jaster
Robert
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D055513:Connective Tissue Growth Factor; D015536:Down-Regulation / Q000187:drug effects*; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D010179:Pancreas / Q000166:cytology* / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D013752:Tetracycline; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
C526317:CCN2 protein, human; C526316:CCN2 protein, rat; D019332:Endothelin-1; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C491589:Socs1 protein, rat; C494081:Stat1 protein, rat; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D007371:Interferon-gamma; D013752:Tetracycline