TGFβ1 induces growth arrest and apoptosis but not ciliated cell differentiation in rat tracheal epithelial cell cultures

Abstract

We are studying the regulation of ciliated cell differentiation using an in vitro model of tracheal regeneration. Previously, we reported that removal of growth stimulating compounds such as epidermal growth factor (EGF) and cholera toxin reduced DNA synthesis and cell number while increasing ciliated cell differentiation (Clark et al., 1995). This result suggested that the induction of growth arrest may stimulate terminal differentiation of airway epithelial cells into ciliated cells. Transforming growth factor beta s (TGF beta s) inhibit epithelial cell proliferation and have also been shown to stimulate epithelial cell differentiation. In this study, the effect of TGF beta 1 on growth and ciliated cell differentiation of rat tracheal epithelial (RTE) cells was examined. TGF beta 1 inhibited [3H]thymidine incorporation by RTE cells in a dose-dependent manner. A 40% inhibition was observed after a 24-h incubation with 10 pM TGF beta 1. Continuous treatment with TGF beta 1 (1-50 pM) also reduced cell number during the time when ciliogenesis occurs. This reduction resulted in part from a loss of cells through exfoliation, in addition to the inhibition of proliferation. The exfoliated cells exhibited several morphological features characteristic of apoptosis, including shrunken cells, condensed and fragmented nuclei, and intact organelles. In addition, electrophoretic analysis of genomic DNA analysis isolated from exfoliated cells demonstrated the presence of a nucleosomal ladder. However, in contrast to the removal of EGF1 treatment with TGF beta 1 for 7 d did not increase ciliated cell differentiation. TGF beta 1 is, therefore, capable of inhibiting proliferation and increasing apoptosis in RTE cells without stimulating ciliated cell differentiation.

Pirfenidone Inhibits Obliterative Airway Disease in Mouse Tracheal Allografts

“…TGF-␤ induces growth arrest and apoptosis of airway epithelial cells. 27 Our laboratory and others have shown that the integrity of the epithelium is critical in preventing the development of the OB-like lesion in the mouse tracheal transplant model. 13,28,29 Stabilization of the epithelium may prevent the formation of granulation tissue.…”

“…The results suggest that pirfenidone may be worthy of further evaluation for its effectiveness in preventing or ameliorating OB in lung transplant recipients. Pirfenidone's mechanism of action probably involves TGF-␤; however, pirfenidone is known to interfere with other mediators of fibrosis [23][24][25][26][27][28][29][30][31][32][33][34] and thus additional investigations of its effects on these and other mediators of rejection are necessary.…”

Connective Tissue Growth Factor Induces Apoptosis in Human Breast Cancer Cell Line MCF-7

“…TGF-␤ stimulates proliferation of mesenchymal cells but inhibits that of endothelial (12) and epithelial cells (13). TGF-␤ is also known to inhibit the proliferation of a variety of cancer cell lines including the human breast cancer cell line MCF-7 (14,15).…”

Prohibitin and Cofilin Are Intracellular Effectors of Transforming Growth Factor β Signaling in Human Prostate Cancer Cells

“…Deregulation of the TGF-h signaling is frequently detected in numerous human malignancies due to either loss of expression or mutational inactivation of its membrane receptors or intracellular Smad proteins (3)(4)(5)(6)(7). TGF-h serves as a growth suppressor by inducing cell growth arrest and promoting apoptosis (8)(9)(10); during tumorigenesis, loss of growth inhibitory control permits tumor cells to use TGF-h for evasion of immune surveillance and gain of metastatic ability (11)(12)(13). The mechanistic network underlying the molecular switch from TGF-h acting as a tumor suppressor to functioning as a tumor promoter during the metastatic process is not clearly defined.…”