Inhibitory effects of interferon-γ 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-γ (IFN-γ) 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-γ signalling. Our data indicate that IFN-γ regulates the expression of two autocrine mediators of PSC activation, connective tissue growth factor and endothelin-1, in a transforming growth factor-β1-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-γ (growth inhibition, induction of apoptosis), and target gene expression. Our data further support the hypothesis that IFN-γ interferes with stellate cell activation in the pancreas and suggest activated STAT1 as an inductor of a quiescent PSC phenotype.