The bcl, NFΚB and p53/p21WAF1 systems are involved in spontaneous apoptosis and in the anti-apoptotic effect of TGF-β or TNF-α on activated hepatic stellate cells

Abstract

Activated hepatic stellate cells (HSC) are thought to play a pivotal role in development of liver fibrosis which takes place in chronic liver diseases. Previous studies have shown that "activated" rat HSC undergo spontaneous apoptosis probably through the CD95/CD95L pathway. TGF-β as well as TNF-α reduced spontaneous apoptosis and CD95L expression. The aim of this study was to investigate the possible mechanisms responsible for the spontaneous apoptosis and for the anti-apoptotic effect of TGF-β and TNF-α on activated HSC. While bcl-2, bax, NFκB and p53 gene expression were spontaneously upregulated, bcl-xL and p21WAF1 gene expression decreased and IκB remained unchanged during the activation process in vitro. TGF-β as well as TNF-α induced activation of NFκB and upregulated bcl-xL. The latter was inhibited by overexpression of IκB. By suppressing spontaneous apoptosis TGF-β as well as TNF-α inhibited p53 gene expression while that of the p21WAF1 gene was increased. We conclude that TGF-β as well as TNF-α may act as surviving factors for activated rat HSC not only through reduction of CD95L gene expression but also by upregulating the anti-apoptotic factors NFκB, bcl-XL and p21WAF1 and by downregulating the proapoptotic factor p53. The interaction with these factors may lead to the generation of new antifibrotic drugs.