Inhibition of epidermal growth factor-like growth factor secretion in tracheobronchial epithelial cells by vitamin A.
Vitamin A deficiency of respiratory tract epithelium results in the phenomenon of squamous cell metaplasia. The mechanisms by which vitamin A regulates airway epithelial cell growth and differentiation are not completely understood. In this study, we focused on the effects of vitamin A (retinol) on growth of human and non-human primate tracheobronchial epithelial (TBE) cells in culture. Retinol and its derivatives have little growth-stimulatory effect on TBE cells that are maintained in primary culture in a serum-free medium supplemented with 6 hormonal supplements: insulin, transferrin, epidermal growth factor (EGF), hydrocortisone, cholera toxin, and bovine hypothalamus extract. However, it was observed that retinol exhibited dose-dependent inhibition of TBE cell growth when EGF was removed from this serum-free culture condition. This inhibition can be reversed if EGF or the conditioned medium of primary TBE cells that are maintained in vitamin A-deficient condition is added. This type of EGF-retinol interacting phenomenon was not observed with the 5 remaining hormonal supplements. Analysis of 125I-labeled EGF binding shows a down-regulation of the high affinity binding sites (Kd = 0.09 nM) on TBE cells grown in the absence of vitamin A. These results suggest that TBE cells are capable of secreting an EGF-like growth factor in the absence of vitamin A. The possibility that transforming growth factor-alpha (TGF-alpha) is involved in this phenomenon is further examined by antibodies specific to TGF-alpha and its binding to an EGF-receptor. Using the TGF-alpha antibody, the presence of a TGF-alpha-specific antigen was found to be 3-fold higher in the conditioned medium obtained from the vitamin A-deficient cultures than that derived from retinol-treated cultures. Furthermore, the antibody neutralizing the TGF-alpha binding to an EGF receptor was able to reduce the DNA synthesis associated with the vitamin A deficiency. These results suggest that vitamin A plays an important regulatory role in the paracrine/autocrine secretion of EGF/TGF-alpha-like mitogen in TBE cell cultures.
Miller
L A
LA
California Regional Primate Research Center, University of California Davis 95616.
Cheng
L Z
LZ
Wu
R
R
D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000187:drug effects* / Q000378:metabolism; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008253:Macaca mulatta; D014132:Trachea / Q000187:drug effects / Q000378:metabolism*; D016211:Transforming Growth Factor alpha / Q000032:analysis / Q000378:metabolism; D014801:Vitamin A / Q000494:pharmacology*
D016211:Transforming Growth Factor alpha; D014801:Vitamin A; D004815:Epidermal Growth Factor; D066246:ErbB Receptors