Transforming growth factor ␤ (TGF-␤) as well as tumor necrosis factor ␣ (TNF-␣) gene expression are up-regulated in chronically inflamed liver. These cytokines were investigated for their influence on apoptosis and proliferation of activated hepatic stellate cells (HSCs). Spontaneous apoptosis in activated HSC was significantly down-regulated by 53% ؎ 8% (P F .01) under the influence of TGF-␤ and by 28% ؎ 2% (P F .05) under the influence of TNF-␣. TGF-␤ and TNF-␣ significantly reduced expression of CD95L in activated HSCs, whereas CD95 expression remained unchanged. Furthermore, HSC apoptosis induced by CD95-agonistic antibodies was reduced from 96% ؎ 2% to 51 ؎ 7% (P F .01) by TGF-␤, and from 96% ؎ 2% to 58 ؎ 2% (P F .01) by TNF-␣, suggesting that intracellular antiapoptotic mechanisms may also be activated by both cytokines. During activation, HSC cultures showed a reduced portion of cells in the G 0 /G 1 phase and a strong increment of G 2 -phase cells. This increment was significantly inhibited (G 1 arrest) by administration of TGF-␤ and/or TNF-␣ to activated cells. In liver sections of chronically damaged rat liver (CCl 4 model), using desmin and CD95L as markers for activated HSC, most of these cells did not show apoptotic signs (TUNEL-negative). Taken together, these findings indicate that TGF-␤ and/or TNF-␣ both inhibit proliferation and also apoptosis in activated HSC in vitro. Both processes seem to be linked to each other, and their inhibition could represent the mechanism responsible for prolonged survival of activated HSC in chronic liver damage in vivo. (HEPATOLOGY 1999;30:196-202.)

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Hepatic stellate cells (HSC), particularly activated HSC, are thought to be the principle matrix-producing cell of the diseased liver. However, other cell types of the fibroblast lineage, especially the rat liver myofibroblasts (rMF), also have fibrogenic potential. A major difference between the two cell types is the different life span under culture conditions. Although nearly no spontaneous apoptosis could be shown in rMF cultures, 18 ± 2% of the activated HSC ( day 7) were apoptotic. Compared with activated HSC, CD95R was expressed in 70% higher amounts in rMF. CD95L could only be detected in activated HSC. Stimulation of the CD95 system by agonistic antibodies (1 ng/ml) led to apoptosis of all rMF within 2 h, whereas activated HSC were more resistant (5.3 h/ 40% of total cells). Although transforming growth factor-β downregulated apoptosis in both activated HSC and rMF, tumor necrosis factor-α (TNF-α) upregulated apoptosis in rMF. Lack of spontaneous apoptosis and CD95L expression in rMF and the different reaction on TNF-α stimulation reveal that activated HSC and rMF belong to different cell populations.

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