Retinoic acid-induced proliferation of lung alveolar epithelial cells: relation with the IGF system.
Retinoids, including retinol and retinoic acid (RA) derivatives, are important molecules for lung growth and homeostasis. The presence of RA receptors and of RA-binding proteins in the alveolar epithelium led to suggest a role for RA on alveolar epithelial cell replication. In the present study, we examined the effects of RA on proliferation of the stem cells of the alveolar epithelium, the type 2 cells. We showed that treatment of serum-deprived type 2 cells with RA led to a stimulation of cell proliferation, with an increase in cell number in a dose-dependent manner. To gain some insights into the mechanisms involved, we studied the effects of RA on the expression of several components of the insulin-like growth factor (IGF) system that have been shown to be associated with the growth arrest of type 2 cells, mainly the IGF-binding protein-2 (IGFBP-2), IGF-II, and the type 2 IGF receptor. We documented a marked decrease in the expression of these components upon RA treatment. Using conditioned media from RA-treated cells, we provided evidence that the proliferative response of type 2 cells to RA was mediated through production of growth factor(s) distinct from IGF-I. We also showed that RA was able to reduce the decrease in cell number observed when type 2 cells were treated with transforming growth factor (TGF)-beta1. These results together with the known stimulatory effect of TGF-beta1 on IGFBP-2 expression led to suggest that RA may be associated with type 2 cell proliferation through mechanisms interfering with the TGF-beta1 pathway.
Department of Pediatric Pulmonology, Institut National de la Santé et de la Recherche Médicale U142, Trousseau Hospital, St. Antoine Medical School, University of Paris, 75012 Paris, France.
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E
Nabeyrat
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Besnard
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Corroyer
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Cazals
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Clement
D000818:Animals; D000831:Animals, Newborn; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000096:biosynthesis*; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis*; D007700:Kinetics; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000502:physiology; D051381:Rats; D017527:Receptor, IGF Type 2 / Q000096:biosynthesis*; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D014212:Tretinoin / Q000494:pharmacology*
D018971:Insulin-Like Growth Factor Binding Protein 2; D017527:Receptor, IGF Type 2; D014212:Tretinoin; D007335:Insulin-Like Growth Factor II; D004247:DNA