Transforming growth factor ? and tumor necrosis factor ? inhibit both apoptosis and proliferation of activated rat hepatic stellate cells

Abstract

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.)

Abrogation of the Antifibrotic Effects of Natural Killer Cells/Interferon-γ Contributes to Alcohol Acceleration of Liver Fibrosis

“…Until now, TGF-β1 was considered as one of the most important survival factors of activated HSCs through the suppression of CD95L expression on HSCs. 41 Our findings in this study suggest that inhibition of NK cell killing of HSCs may also contribute to the important role of TGF-β1 in HSC survival.…”

Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells

“…In addition, direct interactions with ECM components leading to activation of the FAK/PI-3K-dependent survival pathway [26], and the secretion of TIMP-1 thereby preventing MMP-dependent matrix degradation [27] may promote the survival of activated HSC. Finally, autocrine stimulation by cytokines like TGF-β or IGF-1 was regarded as a potential protective mechanism [28,29]. In the in vitro model presented here, co-incubation of HSC with CM of steatotic hepatocytes significantly reduced STS-induced apoptotic cell death.…”

The phenotype of hepatitis B virus-specific T cells differ in the liver and blood in chronic hepatitis B virus infection

“…TNF-␣ is a well-known proinflammatory cytokine and can also induce apoptosis 30,31 or induce activation of hepatic stellate cells that drive fibrosis, as seen in rat models. 32,33 Other studies have shown an association between the infiltration of HBV-tetramer -CD8 ϩ T cells and an elevated ALT in chronic HBV infection but did not specifically look at the relationship of these non-HBV specific CD8 ϩ T cells to histological changes. 2,34 The frequency of intrahepatic HBV-specific TNF-␣ ϩ CD4 ϩ T cells is likely to be much lower than non-HBVspecific CD8 ϩ T cells in chronic HBV infection, but the relative importance of these populations in the generation of liver disease will be important to dissect in future studies.…”