Interferon gamma decreases hepatic stellate cell activation and extracellular matrix deposition in rat liver fibrosis

Abstract

Interferon gamma (IFN-gamma) inhibits in vitro the activation of hepatic stellate cells (HSC), the primary extracellular matrix-producing cells in liver fibrosis. This study was undertaken to determine in vivo the effect of IFN-gamma in the rat model of liver fibrosis induced by dimethylnitrosamine (DMN), where HSC activation represents an early response to cell injury. Rats were killed after 1 or 3 weeks of treatment with DMN, IFN-gamma, DMN + IFN-gamma, or saline. Immunohistochemistry was used to identify proliferating (desmin-positive/bromodeoxyuridine (BrdU)-positive cells) and activated (alpha-smooth-muscle actin [alpha-SMA]-positive cells) HSCs. Collagen deposition was determined colorimetrically and by morphometry. The parenchymal extension of desmin- and actin-positive cells and of fibrotic tissue was measured by point-counting technique and expressed as a percentage of area. Western blot was used to determine laminin and fibronectin accumulation. The levels of messenger RNA (mRNA) for procollagen type I, fibronectin, and laminin were evaluated by Northern blot. No differences were observed in rats treated with either saline or IFN-gamma alone. IFN-gamma reduced HSC activation induced by liver injury, as shown by the decreased number of proliferating HSC and the reduction of parenchymal area occupied by alpha-SMA-positive cells observed in DMN + IFN-gamma-treated animals compared with the DMN group. This was associated with reduced collagen, laminin, and fibronectin accumulation and lower levels of mRNA for procollagen type I, fibronectin, and laminin in the DMN + IFN-gamma group. Thus, this study indicates that IFN-gamma reduces extracellular matrix deposition in vivo by inhibition of HSC activation.

Changes of liver fibrosis in chronic hepatitis C patients with no response to interferon-α therapy: including quantitative assessment by a morphometric method

“…[10][11][12] The role of IFN-α as an antifibrotic agent has also been demonstrated in the human liver. Castilla et al 21 observed a reduction in levels of transforming growth factor (TGF) 1 mRNA expression in the liver, which correlated positively with serum PIIIP levels and histological scores for liver fibrosis in patients with chronic hepatitis C who responded well to IFN-α, suggesting that his therapy may decrease fibrogenesis.…”

“…It has also recently been confirmed in in-vivo experiments that IFN has an antifibrotic effect as well as an antiviral effect. [10][11][12] The aim of this study was to evaluate the antifibrotic activity of IFN-α in CH-C patients with no overt response to therapy by assessing changes in liver biopsy specimens before and after therapy, using both staging and a quantitative histological method. (Table 1) Between 1990 and 1998, 346 consecutive patients with CH-C received IFN therapy in the Gastroenterology Unit of our hospital.…”

Effets hépatiques de l’alcool

“…Un autre méca-nisme par lequel l'alcool augmente la fibrose est son effet inhibiteur sur l'activité des cellules NK dans le foie, entre autres via la production d'IL-10 et de TGF-ß par les monocytes et les cellules étoilées du foie activées elles-mêmes [55]. En effet, les cellules NK présentent une activité antifibrosante en induisant l'apoptose des cellules étoilées du foie en cours d'activation ou senescentes [56][57][58], et en produisant l'IFN-␥, une cytokine qui induit l'arrêt du cycle cellulaire et l'apoptose des cellules étoilées du foie [59,60].…”

What is important to target fibrosis: location, location, location! of cold-shock proteins

“…One of the main questions raised by hepatologists and nephrologists is whether anti-fibrotic activities known from some growth factors, e.g., hepatocyte growth factor (HGF) and interferon-c (IFN-c), may be utilized to revert fibrosis [5,6]. Therefore, clinical trials assessing the effects of IFN-c application on liver fibrosis have been initiated with mixed outcomes [7].…”