Abstract
Keratinocyte growth factor (KGF, or fibroblast growth factor 7) was previously reported to enhance the synthesis of surfactant in alveolar type II cells. We investigated the possible interactions between KGF and a glucocorticoid, dexamethasone (Dex), on surfactant protein (SP) gene expression. In cultured fetal rat type II cells, KGF and Dex induced greater-than-additive stimulating effects on SP-A and SP-B expressions that were enhanced threefold and 30-fold, respectively, but had only additive effects on SP-C expression. Using murine lung epithelial (MLE) cells, KGF increased SP-A, SP-B (up to two-fold), and SP-C (up to threefold) mRNA levels in a dose-dependent way. Dex 10−9 to 10−7 M increased SP-A and SP-B mRNA 1.5-fold and SP-C mRNA two-fold. Consistent with type II cell findings, simultaneous treatment by KGF and Dex induced a synergistic increase of SP-A and SP-B transcripts (three-fold and 4.5-fold, respectively), but not of SP-C transcripts. SP-A protein was present in MLE-15 and was increased about three-fold by KGF plus Dex. Expression study of a reporter gene placed under either the SP-A or the SP-B gene regulatory sequences and transfected in MLE-15 cells indicated that the Dex-KGF synergy was achieved mainly through a transcriptional effect for SP-A, and both transcriptional and nontranscriptional effects for SP-B. For the latter, increased mRNA stability was evidenced with the aid of actinomycin D. The Dex-KGF synergy may have potential interest for diseases associated with surfactant deficiency.
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Abbreviations
- MLE:
-
murine lung epithelial
- KGF:
-
keratinocyte growth factor
- KGFR:
-
keratinocyte growth factor receptor
- Dex:
-
dexamethasone
- SP:
-
surfactant protein
- FBS:
-
fetal bovine serum
- HITES:
-
hydrocortisone-insulin-transferrin-estradiol-selenium
- CAT:
-
chloramphenicol acetyltransferase
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Acknowledgements
The authors thank Drs. S.I. Feinstein and J.A. Whitsett for the gifts of SP-A and SP-B promoter constructs, respectively.
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Supported, in part, by the Fondation pour la Recherche Médicale and by a Legs Poix grant from the Chancellerie des Universités de Paris. O.B.M.-G. was supported by Inserm on a temporary position for foreign researchers “Poste Vert” with the financial assistance of the Région Ile de France. Recombinant KGF was the generous gift of Amgen Biologicals, Thousand Oaks, CA, U.S.A.
A major part of the work was performed in the former Inserm Unit 319, Développement Normal et Pathologique des Fonctions Epithéliales, Université Denis Diderot-Paris 7, Paris, France.
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Mouhieddine-Gueddiche, B., Pinteur, C., Chailley-Heu, B. et al. Dexamethasone Potentiates Keratinocyte Growth Factor-Stimulated SP-A and SP-B Gene Expression in Alveolar Epithelial Cells. Pediatr Res 53, 231–239 (2003). https://doi.org/10.1203/01.PDR.0000047840.77635.AE
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DOI: https://doi.org/10.1203/01.PDR.0000047840.77635.AE
