Transforming growth factor-β induces contraction of activated hepatic stellate cells

Background/Aims: Transforming growth factor-beta (TGF-beta) is a cytokine produced in abundance during liver injury. Recognizing the prominent roles that hepatic stellate cells (HSCs) and TGF-beta play in portal hypertension and fibrogenesis, respectively, we sought to evaluate the effect of TGF-beta on the contractility of activated HSCs. Methods: Spontaneous immortalized cell lines of HSC origin were used in this study. Cells were grown in three-dimensional collagen gel lattice, transferred to 60 mm dishes and exposed to varying concentrations of TGF-beta1 in serum-free medium at 37 degreesC for up to 120 h. The area of the floating gels was measured using a Fluor S-MultiImager (Biorad), the cellular smooth muscle-alpha actin (SMA) content quantified and PKC activation studies conducted. Results: TGF-beta1 induced a time- and dose-dependent decrease in lattice area up to 40% of control (P < 0.05) that reflects the contraction of activated HSCs. This induced contraction was associated with increases in SMA content (3-fold, P < 0.05) and PKC activation (5-fold, P < 0.05) in these cells. Furthermore, pre-incubating with a PKC-epsilon-specific inhibitor completely abrogated the TGF-beta-induced contraction. Conclusions: TGF-beta induces contraction of activated HSCs via an increase in SMA content and a PKC-epsilon-mediated pathway. (C) 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.