The bcl, NF kappa B and p53/p21(WAF1) systems are involved in spontaneous apoptosis and in the anti-apoptotic effect of TGF-beta or TNF-alpha on activated hepatic stellate cells

Activated hepatic stellate cells (HSC) are thought to play a pivotal role i n 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-beta as well as TNF- alpha reduced spontaneous apoptosis and CD95L expression. The aim of this s tudy was to investigate the possible mechanisms responsible for the spontan eous apoptosis and for the anti-apoptotic effect of TGF-beta and TNF-alpha on activated HSC. While bcl-2, bax, NF kappaB and p53 gene expression were spontaneously upregulated, bcl-x(L) and p21(WAF1) gene expression decreased and I kappaB remained unchanged during the activation process in vitro. TG F-P as well as TNF-a induced activation of NF kappaB and upregulated bcl-x( L). The latter was inhibited by overexpression of I kappaB. By suppressing spontaneous apoptosis TGF-beta as well as TNF-alpha inhibited p53 gene expr ession while that of the p21(WAF1) gene was increased. We conclude that TGF -beta as well as TNF-alpha may act as surviving factors for activated rat H SC not only through reduction of CD95L gene expression but also by upregula ting the anti-apoptotic factors NF kappaB, bcl-x(L) and p21(WAF1) and by do wnregulating the proapoptotic factor p53. The interaction with these factor s may lead to the generation of new antifibrotic drugs.