Saile B, Matthes N, Knittel T, Ramadori G
University of Göttingen, Department of Internal Medicine, Section of Gastroenterology and Endocrinology, Göttingen, Germany.
Hepatology. 1999 Jul;30(1):196-202. doi: 10.1002/hep.510300144.
Transforming growth factor beta (TGF-beta) as well as tumor necrosis factor alpha (TNF-alpha) 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 <.01) under the influence of TGF-beta and by 28% +/- 2% (P <.05) under the influence of TNF-alpha. TGF-beta and TNF-alpha 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 <.01) by TGF-beta, and from 96% +/- 2% to 58 +/- 2% (P <.01) by TNF-alpha, suggesting that intracellular antiapoptotic mechanisms may also be activated by both cytokines. During activation, HSC cultures showed a reduced portion of cells in the G0/G1 phase and a strong increment of G2-phase cells. This increment was significantly inhibited (G1 arrest) by administration of TGF-beta and/or TNF-alpha to activated cells. In liver sections of chronically damaged rat liver (CCl4 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-beta and/or TNF-alpha 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.
在慢性炎症肝脏中，转化生长因子β（TGF-β）以及肿瘤坏死因子α（TNF-α）的基因表达上调。研究了这些细胞因子对活化肝星状细胞（HSC）凋亡和增殖的影响。在TGF-β的影响下，活化HSC中的自发凋亡显著下调了53%±8%（P<.01），在TNF-α的影响下下调了28%±2%（P<.05）。TGF-β和TNF-α显著降低了活化HSC中CD95L的表达，而CD95的表达保持不变。此外，TGF-β将CD95激动性抗体诱导的HSC凋亡从96%±2%降低到51±7%（P<.01），TNF-α将其从96%±2%降低到58±2%（P<.01），这表明两种细胞因子也可能激活细胞内抗凋亡机制。在活化过程中，HSC培养物中处于G0/G1期的细胞比例降低，G2期细胞大量增加。向活化细胞施用TGF-β和/或TNF-α可显著抑制这种增加（G1期阻滞）。在慢性损伤大鼠肝脏（CCl4模型）的肝切片中，使用结蛋白和CD95L作为活化HSC的标志物，这些细胞中的大多数未显示凋亡迹象（TUNEL阴性）。综上所述，这些发现表明TGF-β和/或TNF-α在体外均抑制活化HSC的增殖和凋亡。这两个过程似乎相互关联，它们的抑制可能代表了体内慢性肝损伤中活化HSC长期存活的机制。
