Stolz D B, Michalopoulos G K
Department of Pathology, University of Pittsburgh School of Medicine, Pennsylvania 15261, USA.
J Cell Physiol. 1997 Jan;170(1):57-68. doi: 10.1002/(SICI)1097-4652(199701)170:1<57::AID-JCP7>3.0.CO;2-K.
The ability of TGF-beta 1 (transforming growth factor-beta 1) to suppress growth factor induced proliferation of many cell types in vitro is well documented; however, TGF-beta 1 increases within a similar time frame as the hepatocyte mitogens HGF (hepatocyte growth factor), EGF (epidermal growth factor), and TGF-alpha (transforming growth factor-alpha) prior to hepatocyte proliferation during liver regeneration. This has raised the issue that TGF-beta 1 may have effects on hepatocytes additional to mito-inhibition and that these effects may be relevant to the regenerative process. To this end, we examined the effect of TGF-beta 1 on both the mitogenesis and the motility of growth factor stimulated primary rat hepatocytes and the hepatoblastoma cell line HepG2 in vitro. TGF-beta 1 significantly enhanced the chemotactic motility of EGF or TGF-alpha, and not HGF, stimulated hepatocytes on a collagen I substratum. TGF-beta 1 was not chemotactic when added alone and decreased the DNA synthesis of all hepatocyte cultures to near control levels. HepG2 cells were chemotactic toward HGF, EGF, and TGF-beta 1 alone and displayed an additive chemotactic response when TGF-beta 1 was added to either HGF or EGF. Additionally, HepG2 cells were refractory to the growth stimulatory effects of HGF or EGF and the growth inhibitory effects of TGF-beta 1. Hepatocytes plated onto other collagen-containing substrates (collagen IV, Matrigel, or ECL, an entactin-collagen IV-laminin matrix), but not on fibronectin or laminin alone, also displayed enhanced EGF stimulated motility by TGF-beta 1. The data indicate that an additional, novel role for TGF-beta 1 during liver tissue remodeling following PHx may include the synergistic enhancement EGF stimulated hepatocyte motility responses, and this enhancement is observed only on collagen-containing extracellular matrices.
转化生长因子β1（TGF-β1）在体外抑制多种细胞类型生长因子诱导的增殖能力已有充分记录；然而，在肝再生过程中肝细胞增殖之前，TGF-β1在与肝细胞有丝分裂原肝细胞生长因子（HGF）、表皮生长因子（EGF）和转化生长因子α（TGF-α）相似的时间范围内增加。这就提出了一个问题，即TGF-β1除了有丝分裂抑制作用外，可能对肝细胞还有其他作用，并且这些作用可能与再生过程相关。为此，我们在体外研究了TGF-β1对生长因子刺激的原代大鼠肝细胞和肝癌细胞系HepG2的有丝分裂和运动性的影响。TGF-β1显著增强了EGF或TGF-α（而非HGF）刺激的肝细胞在I型胶原基质上的趋化运动性。单独添加时，TGF-β1没有趋化作用，并将所有肝细胞培养物的DNA合成降低至接近对照水平。HepG2细胞单独对HGF、EGF和TGF-β1有趋化作用，当将TGF-β1添加到HGF或EGF中时，显示出累加趋化反应。此外，HepG2细胞对HGF或EGF的生长刺激作用以及TGF-β1的生长抑制作用均不敏感。接种到其他含胶原底物（IV型胶原、基质胶或ECL，一种内联蛋白 - IV型胶原 - 层粘连蛋白基质）上的肝细胞，但不是单独接种到纤连蛋白或层粘连蛋白上的肝细胞，也显示出TGF-β1增强的EGF刺激的运动性。数据表明，在部分肝切除（PHx）后肝组织重塑过程中，TGF-β1的另一个新作用可能包括协同增强EGF刺激的肝细胞运动反应，并且这种增强仅在含胶原的细胞外基质上观察到。
