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Glucocorticoid Regulation of Human Pulmonary Surfactant Protein-B mRNA Stability Involves the 3'-Untranslated Region

¹ Department of Pediatrics, Division of Neonatal-Perinatal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas

Correspondence and requests for reprints should be addressed to Joseph L. Alcorn, Jr., Ph.D., Department of Pediatrics, University of Texas-Houston Medical School, 6431 Fannin, suite 3.222, Houston, TX 77030. E-mail: Joseph.L.Alcorn{at}uth.tmc.edu

Expression of pulmonary surfactant, a complex mixture of lipids and proteins that acts to reduce alveolar surface tension, is developmentally regulated and restricted to lung alveolar type II cells. The hydrophobic protein surfactant protein-B (SP-B) is essential in surfactant function, and insufficient levels of SP-B result in severe respiratory dysfunction. Glucocorticoids accelerate fetal lung maturity and surfactant synthesis both experimentally and clinically. Glucocorticoids act transcriptionally and post-transcriptionally to increase steady-state levels of human SP-B mRNA; however, the mechanism(s) by which glucocorticoids act post-transcriptionally is unknown. We hypothesized that glucocorticoids act post-transcriptionally to increase SP-B mRNA stability via sequence-specific mRNA–protein interactions. We found that glucocorticoids increase SP-B mRNA stability in isolated human type II cells and in nonpulmonary cells, but do not alter mouse SP-B mRNA stability in a mouse type II cell line. Deletion analysis of an artificially-expressed SP-B mRNA indicates that the SP-B mRNA 3'-untranslated region (UTR) is necessary for stabilization, and the region involved can be restricted to a 126-nucleotide-long region near the SP-B coding sequence. RNA electrophoretic mobility shift assays indicate that cytosolic proteins bind to this region in the absence or presence of glucocorticoids. The formation of mRNA:protein complexes is not seen in other regions of the SP-B mRNA 3'-UTR. These results indicate that a specific 126-nucleotide region of human SP-B 3'-UTR is necessary for increased SP-B mRNA stability by glucocorticoids by a mechanism that is not lung cell specific and may involve mRNA–protein interactions.

Key Words: surfactant • SP-B • glucocorticoid • mRNA stability • 3'-untranslated region

CLINICAL RELEVANCE The research begins to define the mechanism by which corticosteroids increase pulmonary surfactant protein B (SP-B) mRNA stability, which may lead to treatments specifically designed to augment SP-B protein levels in immature lungs.