Interferon gamma inhibits lipocyte activation and extracellular matrix mRNA expression during experimental liver injury: implications for treatment of hepatic fibrosis.
BACKGROUND
A central feature of liver injury involves activation of hepatic lipocytes (perisinusoidal cells), a process characterized by their morphologic transformation to myofibroblast-like cells. Important features of this process include new expression of smooth muscle alpha actin and production of increased amounts of extracellular matrix. Interferon gamma is a cytokine with immunomodulatory and antifibrotic properties that has potent effects on lipocytes in a culture model of activation. The aim of this study was to determine if interferon gamma inhibited lipocyte activation in an in vivo model of liver injury and whether this effect resulted in an overall reduction in hepatic fibrosis.


METHODS
Liver injury (with ensuing fibrosis) was induced by carbon tetrachloride. Interferon gamma was infused continuously by osmotic pump during the induction of liver fibrosis, after which lipocytes were isolated and features of lipocyte activation were examined. Finally, whole liver type I collagen mRNA was quantitated.


RESULTS
Carbon tetrachloride caused histological fibrosis, which was significantly reduced on a quantitative basis by interferon gamma. Immunocytochemical analysis of livers from animals treated with interferon gamma demonstrated a significant reduction in the number of desmin positive cells (lipocytes) in portal and noncentral lobular areas as well as in bands of fibrosis, consistent with reduced lipocyte proliferation. Using discontinuous density centrifugation, two populations of lipocytes were isolated and characterized: one migrating in the upper layer of the gradient and another to the lower layer. Interferon gamma markedly reduced smooth muscle alpha actin expression (by immunoblot) in upper layer lipocytes and had significant inhibitory but less dramatic effects on lower layer lipocytes. Interferon gamma also reduced collagen I mRNA to 36% (p < 0.001, interferon gamma versus control) and 46% (p < 0.01) of control values in upper and lower layer lipocyte samples, respectively. Effects of interferon gamma on expression of cellular fibronectin mRNA were similar. Smooth muscle actin as well as type I collagen and cellular fibronectin mRNA were more abundant in lower than upper layer lipocytes in both control and interferon gamma treated animals. Finally, interferon gamma reduced collagen I mRNA in whole liver specimens to 36% of control values (p < 0.005, for interferon gamma compared to control, n = 6).


CONCLUSIONS
The data indicate that interferon gamma inhibits lipocyte activation and extracellular matrix production in vivo during liver injury, which results in an overall decrease in hepatic fibrosis. Further, the data demonstrate heterogeneity in lipocytes during activation and identify a novel population of markedly activated lipocytes.
Department of Medicine, San Francisco General Hospital, University of California 94110, USA.
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Rockey
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Chung
D017667:Adipocytes / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D003094:Collagen / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism* / Q000473:pathology; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D012333:RNA, Messenger; D007371:Interferon-gamma; D003094:Collagen