Grande J P, Melder D C, Zinsmeister A R
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
J Lab Clin Med. 1997 Nov;130(5):476-86. doi: 10.1016/s0022-2143(97)90124-4.
Transforming growth factor-beta1 (TGF-beta1) is well recognized as a potent mediator of both fibrillar (collagen type I) and basement membrane (collagen type IV) production. However, tissue injury is characterized by the concomitant expression of many cytokines and/or growth factors in addition to TGF-beta1, and the ultimate extent of extracellular-matrix (ECM) deposition may reflect the interacting effects of TGF-beta1 and these other cytokines and/or growth factors. We, therefore, sought to determine whether other cytokines and/or growth factors, known to be produced after tissue injury, are capable either alone or in combination with TGF-beta1 of modulating collagen gene expression. Collagen type I and collagen type IV gene expression was assessed in NIH-3T3 cells, a murine fibroblast-like cell line that responds to TGF-beta1, with increases in both collagen type I and collagen type IV production. TGF-beta1 coordinately induced production of collagen type IV messenger ribonucleic acid (mRNA) to a level 3.8-fold above its baseline value (p < 0.001) and collagen type I mRNA to a level 2.6-fold above its baseline value (p < 0.001). Of the other cytokines and/or growth factors tested, only epidermal growth factor (EGF) had significant effects on collagen mRNA expression. We report the novel observation that EGF significantly induced collagen type IV mRNA (3.0-fold; p < 0.001) but did not alter collagen type I mRNA expression. Platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and insulin-like growth factor-1 (IGF-1) did not alter the expression of mRNA for collagen type IV or collagen type I. Addition of TGF-beta1 to cytokine- and/or growth factor-treated cells increased both collagen type IV and collagen type I mRNA levels. However, collagen type IV mRNA levels were similar in cultures given TGF-beta1 alone and cultures given TGF-beta1 with other cytokines and/or growth factors; there were no additive, synergistic, or antagonistic effects after coadministration of TGF-beta1 and other cytokines and/or growth factors. With regard to collagen type I mRNA expression, all cytokines and/or growth factors tested, with the exception of TNF-alpha, had no effect on collagen type I mRNA levels in TGF-beta1-treated cultures. Importantly, TNF-alpha antagonized the stimulatory effect of TGF-beta1 on collagen type I mRNA levels. These observations support a dominant role for TGF-beta1 in stimulating coordinate expression of collagen type I and collagen type IV mRNAs by NIH-3T3 cells; EGF and TNF-alpha are capable of inducing divergent expression of the genes for these two types of collagen.
转化生长因子-β1（TGF-β1）是公认的纤维状（I型胶原）和基底膜（IV型胶原）产生的强效介质。然而，组织损伤的特征是除了TGF-β1之外，还伴随有多种细胞因子和/或生长因子的表达，细胞外基质（ECM）沉积的最终程度可能反映了TGF-β1与这些其他细胞因子和/或生长因子的相互作用。因此，我们试图确定组织损伤后已知产生的其他细胞因子和/或生长因子，单独或与TGF-β1联合是否能够调节胶原基因表达。在NIH-3T3细胞中评估I型胶原和IV型胶原基因的表达，NIH-3T3细胞是一种对TGF-β1有反应的鼠成纤维细胞样细胞系，I型胶原和IV型胶原的产生均增加。TGF-β1协同诱导IV型胶原信使核糖核酸（mRNA）的产生，使其水平比基线值高3.8倍（p<0.001），I型胶原mRNA水平比基线值高2.6倍（p<0.001）。在测试的其他细胞因子和/或生长因子中，只有表皮生长因子（EGF）对胶原mRNA表达有显著影响。我们报告了一个新的观察结果，即EGF显著诱导IV型胶原mRNA（3.0倍；p<0.001），但不改变I型胶原mRNA表达。血小板衍生生长因子（PDGF）、碱性成纤维细胞生长因子（bFGF）、肿瘤坏死因子-α（TNF-α）、白细胞介素-1（IL-1）和胰岛素样生长因子-1（IGF-1）均未改变IV型胶原或I型胶原mRNA的表达。将TGF-β1添加到细胞因子和/或生长因子处理的细胞中，可增加IV型胶原和I型胶原mRNA水平。然而，单独给予TGF-β1的培养物和给予TGF-β1与其他细胞因子和/或生长因子的培养物中，IV型胶原mRNA水平相似；TGF-β1与其他细胞因子和/或生长因子共同给药后，没有相加、协同或拮抗作用。关于I型胶原mRNA表达，除TNF-α外，所有测试的细胞因子和/或生长因子对TGF-β1处理的培养物中的I型胶原mRNA水平均无影响。重要的是，TNF-α拮抗TGF-β1对I型胶原mRNA水平的刺激作用。这些观察结果支持TGF-β1在刺激NIH-3T3细胞协调表达I型胶原和IV型胶原mRNA方面起主导作用；EGF和TNF-α能够诱导这两种胶原基因的不同表达。
