Nettesheim P, Ferriola P C, Robertson A T, Iwanaga T, Steigerwalt R, Rundhaug J E
Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Princess Takamatsu Symp. 1991;22:171-81.
The role of the peptide growth factors transforming growth factor alpha (TGF alpha) and transforming growth factor beta (TGF beta) in the regulation of proliferation of normal and transformed airway epithelial cells was studied. Normal as well as transformed rat tracheal epithelial (RTE) cell cultures secrete similar amounts of TGF alpha during logarithmic growth. Once normal RTE cell cultures reach the plateau phase of growth, they down-regulate TGF alpha expression at the RNA and protein level; in contrast, transformed cells do not down-regulate TGF alpha. Using neutralizing TGF alpha antiserum and a tyrphostin TGF alpha/EGF receptor tyrosine kinase inhibitor, we show that the secreted TGF alpha is utilized by both normal and transformed cells as an autocrine mitogenic factor. Normal RTE cells are highly sensitive to the growth inhibitory effects of TGF beta, particularly during early phases of logarithmic growth. At late logarithmic and plateau phases of proliferation, cultures of normal RTE cells secrete large amounts of TGF beta. That the endogenous TGF beta is exerting growth inhibitory effects can be demonstrated by adding TGF beta antisera to the cultures which causes a burst of proliferation. Many transformed RTE cell lines exhibit a markedly reduced sensitivity to the growth inhibitory effects of TGF beta. However, the cells remain responsive to regulation of ECM genes by TGF beta. The transformed cell lines examined secrete less than one tenth the amount of TGF beta of normal cells. Our studies show that the autocrine TGF beta growth restraining mechanism is inoperative in many of the RTE cell transformants. We conclude, therefore, that alterations in TGF alpha and TGF beta regulation of cell proliferation are important factors contributing to the abnormal growth behavior of transformed RTE cells.
研究了肽生长因子转化生长因子α（TGFα）和转化生长因子β（TGFβ）在调节正常和转化气道上皮细胞增殖中的作用。正常和转化的大鼠气管上皮（RTE）细胞培养物在对数生长期分泌相似量的TGFα。一旦正常RTE细胞培养物达到生长平台期，它们会在RNA和蛋白质水平下调TGFα表达；相反，转化细胞不会下调TGFα。使用中和TGFα抗血清和一种酪氨酸磷酸化酶TGFα/EGF受体酪氨酸激酶抑制剂，我们表明分泌的TGFα被正常和转化细胞用作自分泌促有丝分裂因子。正常RTE细胞对TGFβ的生长抑制作用高度敏感，尤其是在对数生长期的早期阶段。在对数生长期后期和增殖平台期，正常RTE细胞培养物分泌大量TGFβ。通过向培养物中添加TGFβ抗血清可导致增殖爆发，这可以证明内源性TGFβ发挥着生长抑制作用。许多转化的RTE细胞系对TGFβ的生长抑制作用表现出明显降低的敏感性。然而，这些细胞仍然对TGFβ调节细胞外基质基因有反应。所检测的转化细胞系分泌的TGFβ量不到正常细胞的十分之一。我们的研究表明，自分泌TGFβ生长抑制机制在许多RTE细胞转化体中不起作用。因此，我们得出结论，TGFα和TGFβ对细胞增殖调节的改变是导致转化RTE细胞异常生长行为的重要因素。
