Modulation of Urokinase-Type Plasminogen Activator by Transforming Growth Factor β1 in Acetaldehyde-Activated Hepatic Stellate Cells

Abstract

The aim of this study was to determine whether transforming growth factor-β₁ (TGF-β₁) induces the synthesis, release and gene expression of urokinase-type plasminogen activator (uPA) in hepatic stellate cells. In addition to stimulating collagen production, TGF-β₁ induced the morphological and phenotypical changes characteristic of hepatic stellate cell activation. However, these changes accentuated in cells previously activated with acetaldehyde. TGF-β₁ increased to 2-fold uPA activity in lysates from quiescent cells, and to 3.5-fold in activated cells, and induced uPA gene expression to the same extent in both activated and non-activated cells. TGF-β₁ had a modest stimulatory action on the release of uPA into the conditioned medium, but reduced acetaldehyde-induced release, as demonstrated by Western blot analysis. In accord, whereas TGF-β₁ produces no effect on uPA activity in the conditioned media from quiescent cells, it significantly reduces the stimulatory action of acetaldehyde. These results show that the activity and gene expression of uPA are regulated by both acetaldehyde and TGF-β₁ and that the proteolytic activity in the extracellular space is reduced by the influence of TGF-β₁. Further studies on the molecular mechanisms responsible for the regulation of the plasminogen system by TGF-β₁ and other molecules in the presence of acetaldehyde will contribute to a better understanding of the processes involved in fibrogenesis.