Pratsinis Harris, Giannouli Christina C, Zervolea Irene, Psarras Stelios, Stathakos Dimitri, Kletsas Dimitris
Laboratory of Cell Proliferation and Aging, Institute of Biology, National Center for Scientific Research Demokritos, 153 10 Athens, Greece.
Wound Repair Regen. 2004 May-Jun;12(3):374-83. doi: 10.1111/j.1067-1927.2004.12305.x.
Since pronounced differences exist between the fetal and adult repair processes, we studied the proliferative response of skin fibroblasts from these two stages to transforming growth factor-beta (TGF-beta), a cytokine with a broad range of activities in tissue repair. Here, we present evidence that TGF-beta inhibits fetal human skin fibroblasts, while it is stimulatory for adult ones. This proliferative effect of TGF-beta was found to be concentration- dependent, but isoform-independent. Furthermore, even a transient exposure of the cells to this growth factor was sufficient to exert its stimulatory or inhibitory action. Accordingly, we have studied the immediate responses provoked by TGF-beta in major signaling pathways, and we have found that it induces a rapid activation of the SMAD pathway, i.e., phosphorylation and nuclear translocation of SMAD2, followed by dephosphorylation, most probably due to degradation by the proteasome. However, similar intensity and kinetics of this activation have been observed in both fetal and adult fibroblasts. On the other hand, curcumin, a natural product with wound healing properties that inhibits several intracellular signaling pathways, was found to completely abrogate the inhibitory effect of TGF-beta1 on human fetal skin fibroblasts, without affecting the stimulatory action on fibroblasts from adult donors. In conclusion, there is a major radical in the proliferative response of fetal and adult human skin fibroblasts to TGF-beta, possibly reflecting the different repair strategies followed in these two stages of development.
由于胎儿和成人的修复过程存在明显差异，我们研究了这两个阶段的皮肤成纤维细胞对转化生长因子-β（TGF-β）的增殖反应，TGF-β是一种在组织修复中具有广泛活性的细胞因子。在此，我们提供证据表明，TGF-β抑制胎儿人皮肤成纤维细胞，而对成人皮肤成纤维细胞具有刺激作用。TGF-β的这种增殖作用呈浓度依赖性，但与异构体无关。此外，即使细胞短暂暴露于这种生长因子也足以发挥其刺激或抑制作用。因此，我们研究了TGF-β在主要信号通路中引发的即时反应，发现它能诱导SMAD通路的快速激活，即SMAD2的磷酸化和核转位，随后发生去磷酸化，这很可能是由于蛋白酶体降解所致。然而，在胎儿和成人成纤维细胞中均观察到这种激活具有相似的强度和动力学。另一方面，姜黄素是一种具有伤口愈合特性的天然产物，能抑制多种细胞内信号通路，它被发现可完全消除TGF-β1对人胎儿皮肤成纤维细胞的抑制作用，而不影响对成人供体成纤维细胞的刺激作用。总之，胎儿和成人皮肤成纤维细胞对TGF-β的增殖反应存在重大差异，这可能反映了这两个发育阶段所采用的不同修复策略。
