Regulation of surfactant protein gene expression by retinoic acid metabolites.
Surfactant-associated proteins (SP) play an important role in the function of pulmonary surfactant. We have previously shown that SP-B mRNA is increased whereas SP-A and SP-C mRNA are decreased by all-trans-retinoic acid (RA) in a dose-dependent manner in human fetal lung explants. All-trans-RA binds primarily to the retinoic acid receptors (RARs) and 9-cis-RA binds primarily to the retinoid X receptors (RXRs). Because the fetal lung contains RXRs, we hypothesized that 9-cis-RA regulates surfactant protein gene expression in lung epithelial cells. H441 human lung adenocarcinoma cells, which synthesize SP-A and SP-B mRNA and protein, were treated with either all-trans-RA or 9-cis-RA (10(-10) to 10(-6) M) for 24 h. Neither all-trans-RA nor 9-cis-RA had an effect on SP-A mRNA levels in the H441 cells. All-trans-RA (10(-6) M) significantly increased SP-B mRNA levels in the H441 cells and 9-cis-RA had a smaller, not statistically significant effect. Human fetal lung explants were treated with 9-cis-RA for 6 d. 9-cis-RA did not significantly increase SP-B mRNA levels, significantly inhibited SP-A mRNA levels at all concentrations tested, and significantly inhibited SP-C mRNA levels at 10(-6) M in the human fetal lung explants. Both all-trans-RA (10(-6) M) and 9-cis-RA (10(-6) M) significantly increased SP-B protein levels in the human fetal lung explants. Together, these results are suggestive that all-trans-RA directly regulates SP-B gene expression in human pulmonary epithelial cells. In addition, the inhibitory effect of all-trans-RA and 9-cis-RA on SP-A mRNA levels in pulmonary epithelial cells is probably an indirect effect mediated by other cell types present in fetal lung tissue.
George
T N
TN
Department of Pediatrics, University of Iowa College of Medicine, Iowa City 52242, USA.
Snyder
J M
JM
D000230:Adenocarcinoma; D000077556:Alitretinoin; D000704:Analysis of Variance; D006801:Humans; D007700:Kinetics; D008168:Lung / Q000196:embryology / Q000378:metabolism*; D008175:Lung Neoplasms; D009924:Organ Culture Techniques; D011510:Proteolipids / Q000096:biosynthesis*; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis; D018168:Receptors, Retinoic Acid / Q000502:physiology; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D011510:Proteolipids; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D000077556:Alitretinoin; D014212:Tretinoin