Tetrandrine inhibits activation of rat hepatic stellate cells stimulated by transforming growth factor-β in vitro via up-regulation of Smad 7

Tetrandrine is a bisbenzylisoquinoline alkaloid derived from the root of a Chinese herbal medicine Stephania tetrandra S. Moore, which has been used traditionally for the treatment of hepatofibrogenic disease in China for several decades. In the present study, the inhibitory effects of tetrandrine lower concentrations (0.25, 0.5, 1, 2 mg/L) on culture-activation and transforming growth factor-beta(1) (TGF-beta(1))-stimulated activation of quiescent rat hepatic stellate cells (HSCs) in vitro were assessed, and the possible relations between the underlying mechanism of these effects and TGF-beta signaling via its receptors were investigated. As shown by the examination of alpha-SMA using immunocytochemical staining or Western blot, tetrandrine inhibited both culture-activation and TGF-beta(1) -stimulated activation of HSCs. Further investigations revealed that, in this process, TGF-beta(1), mRNA expression was suppressed significantly in contrast to an up-regulation of Smad 7, while the expressions of type I and type II TGF-beta(1) receptors and Smad 3 inRNA were insignificantly changed by tetrandrine. These results suggest that tetrandrine at lower concentrations has a significant inhibiting effect on culture-activation and TGF-beta(1) -stimulated activation of rat HSCs, and that it may be due to an up-regulation of Smad 7 which in turn blocks TGF-beta(1), expression and its downstream signaling. (C) 2005 Elsevier Ireland Ltd. All rights reserved.