Transforming growth factor-beta 1 (TGF beta 1) enhances apoptosis in human papillomavirus type 16-immortalized human ectocervical epithelial cells.
Transforming growth factor beta (TGF beta) is a potent inhibitor of epithelial cell growth. In the present study TGF beta 1 modulation of human ectocervical epithelial cell growth and differentiation is evaluated using an HPV16-immortalized human ectocervical cell line, ECE16-1. These cells were found to contain a high-affinity receptor for TGF beta 1 (Kd = 75 pM). TGF beta (10-500 pg/ml) suppressed ECE16-1 growth and [3H]thymidine incorporation in a dose-dependent manner. Growth inhibition was reversible at TGF beta 1 concentrations of 100 pg/ml or less. At higher concentrations of TGF beta 1, treatment for longer than 2 days induced irreversible growth inhibition. In addition to its effects on cell growth, TGF beta 1 treatment increased apoptosis in ECE16-1 cells as measured by an increase in cornified envelope formation, flow cytometry, and DNA fragmentation. Apoptosis was enhanced at doses > or = 100 pg/ml. There was a highly significant increase in the activity of tissue transglutaminase, an enzyme believed to play an important role in apoptosis. This increase in transglutaminase activity was paralleled by a TGF beta 1-stimulated increase in fibronectin levels. Transglutaminase and fibronectin have been shown to associate during tissue remodeling. These data suggest that TGF beta 1 may act as an important paracrine/autocrine factor to stimulate normal cervical remodeling and to limit HPV16-immortalized cervical cell progression by stimulating apoptosis. The induction of fibronectin and tissue transglutaminase suggests that the TGF beta 1 pathway of cell death differs from that of normal ectocervical epithelial cell differentiation, which is mediated by epidermal transglutaminase.
Rorke
E A
EA
Department of Environmental Health Sciences, Case Western Reserve University, Cleveland, Ohio 44106.
Jacobberger
J W
JW
D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002584:Cervix Uteri / Q000166:cytology* / Q000187:drug effects / Q000502:physiology / Q000821:virology; D004247:DNA / Q000096:biosynthesis / Q000378:metabolism; D004847:Epithelial Cells; D005260:Female; D005353:Fibronectins / Q000096:biosynthesis; D006801:Humans; D007633:Keratins / Q000032:analysis; D007700:Kinetics; D027383:Papillomaviridae / Q000502:physiology; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*; D011503:Transglutaminases / Q000378:metabolism
D005353:Fibronectins; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D007633:Keratins; D004247:DNA; D011503:Transglutaminases