Contribution of sinusoidal endothelial liver cells to liver fibrosis: Expression of transforming growth factor-β1 receptors and modulation of plasmin-generating enzymes by transforming growth factor-β1

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Abstract
Transforming growth factor-βH1 is an important cytokine in the pathophysiology of liver fibrosis, stimulating the production of extracellular matrix. Whether this cytokine can also control the degradation of matrix proteins in liver cells has not been investigated. Because plasmin is an important protease for the degradation of matrix glycoproteins, we investigated whether sinusoidal endothelial liver cells could contribute to fibrosing liver disease through the modulation of plasmin-generating enzymes in response to transforming growth factor-β1. Sinusoidal endothelial cells from guinea pig liver were investigated in pure monolayer culture. Using 125I-labelled transforming growth factor-β, we demonstrated high-affinity binding sites on sinusoidal endothelial cells at a density of 9.3 × 102 per cell, and a dissociation constant of about 5.5 × 10−11 mol/L. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed the known three classes of membrane receptors for transforming growth factor-β. Using biosynthetic labeling of proteins with 35S-methionine, immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, we showed that sinusoidal endothelial cells produce and secrete plasminogen activator inhibitor type 1 from the beginning of culture. Treatment of confluent cell cultures for 24 hr with transforming growth factor-β1 increased synthesis and release of plasminogen activator inhibitor type 1. The response was almost maximal at a concentration of 1 ng transforming growth factor-β/ml and paralleled the increased synthesis of fibronectin. On reverse fibrin autography we proved that transforming growth factor-β1 stimulated the release of functionally active plasminogen activator inhibitor type 1. On the other hand, transforming growth factor-β1 decreased in a dose-dependent manner the release of plasminogen activators as shown by fibrin autography. From these studies it is evident that sinusoidal endothelial liver cells respond to transforming growth factor-β1 in a fibrogenic manner, reducing the plasmin-generating potential, resulting in decreased proteolysis of extra-cellular matrix glycoproteins. Therefore we postulated that sinusoidal endothelial cells may participate in early stages of fibrotic liver disease such as capillarization and collagenization of liver sinusoids. (HEPATOLOGY 1993;18:937-944).