Department of Pharmacology, Basic Medical College of Wuhan University, Wuhan 430071, China.
Eur J Pharmacol. 2011 Jan 15;650(2-3):656-62. doi: 10.1016/j.ejphar.2010.10.057. Epub 2010 Oct 31.
During the course of liver fibrogenesis, hepatic stellate cell (HSC) proliferation as well as subsequent synthesis of excessive extracellular matrix components is known to be the central events. Thus, factors that could limit HSC proliferation are potential anti-fibrotic agents. The aim of this study was to investigate the effects of indole-3-carbinol (I3C), a nutritional component derived from Brassica family vegetables, on the proliferation of cultured HSC and to clarify the underline molecular mechanism. HSC-T6, an activated rat HSC line, was treated with I3C (50, 100 and 200 μM) for 24 h. The results indicated that I3C can significantly inhibit HSC proliferation in a concentration-dependent manner with or without platelet-derived growth factor-BB (PDGF-BB) stimulation (P<0.01). I3C could also block HSC in the G(0)/G(1) phase from entering the S phase. The expressions of α-smooth muscle actin in HSC treated with I3C, were significantly decreased at levels of protein and mRNA (P<0.01). In addition, the type I collagen level, cyclin D(1) and cyclin-dependent kinase 4 mRNA expressions, intracellular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and reactive oxygen species generation were significantly decreased by I3C (P<0.05). We also observed that the phosphorylated p38 MAPK in HSC-T6 was inhibited by I3C in a concentration-dependent manner; however, the phosphorylated ERK1/2 was unaltered. In conclusion, I3C could inhibit the proliferation of HSC by blocking the NADPH oxidase/reactive oxygen species/p38 MAPK signal pathway. These findings suggest that dietary I3C might play a novel role in prevention and treatment of chronic liver diseases.
在肝纤维化的过程中，肝星状细胞（HSC）的增殖以及随后过量细胞外基质成分的合成被认为是中心事件。因此，能够限制 HSC 增殖的因素是潜在的抗纤维化剂。本研究旨在探讨吲哚-3-甲醇（I3C），一种来自 Brassica 科蔬菜的营养成分，对培养的 HSC 增殖的影响，并阐明其潜在的分子机制。HSC-T6，一种激活的大鼠 HSC 系，用 I3C（50、100 和 200 μM）处理 24 小时。结果表明，I3C 可以显著抑制 HSC 的增殖，呈浓度依赖性，无论是否有血小板衍生生长因子-BB（PDGF-BB）刺激（P<0.01）。I3C 还可以阻止 HSC 从 G0/G1 期进入 S 期。用 I3C 处理的 HSC 中的α-平滑肌肌动蛋白的表达，在蛋白质和 mRNA 水平上均显著降低（P<0.01）。此外，I3C 还显著降低了 I 型胶原水平、细胞周期蛋白 D1 和细胞周期蛋白依赖性激酶 4 mRNA 的表达、细胞内烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶活性和活性氧的产生（P<0.05）。我们还观察到，I3C 以浓度依赖性方式抑制 HSC-T6 中的磷酸化 p38 MAPK；然而，磷酸化 ERK1/2 没有改变。总之，I3C 可以通过阻断 NADPH 氧化酶/活性氧/p38 MAPK 信号通路来抑制 HSC 的增殖。这些发现表明，饮食中的 I3C 可能在预防和治疗慢性肝病方面发挥新的作用。
