Dexamethasone potentiates keratinocyte growth factor-stimulated SP-A and SP-B gene expression in alveolar epithelial cells.
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 three-fold 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 three-fold) 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.
Mouhieddine-Gueddiche
O Banine
OB
Inserm U492, Physiopathologie et Thérapeutique Respiratoires, Université-Paris XII, Créteil, France.
Pinteur
Claudie
C
Chailley-Heu
Bernadette
B
Barlier-Mur
Anne-Marie
AM
Clement
Annick
A
Bourbon
Jacques R
JR
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002460:Cell Line; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004357:Drug Synergism; D004847:Epithelial Cells; D005333:Fetus; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D017930:Genes, Reporter / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008970:Molecular Weight; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects / Q000196:embryology; D037662:Pulmonary Surfactant-Associated Protein A / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D037701:Pulmonary Surfactant-Associated Protein B / Q000235:genetics*; D037721:Pulmonary Surfactant-Associated Protein C / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000096:biosynthesis; D014162:Transfection
C496454:Fgf7 protein, mouse; C496455:Fgf7 protein, rat; D037662:Pulmonary Surfactant-Associated Protein A; D037701:Pulmonary Surfactant-Associated Protein B; D037721:Pulmonary Surfactant-Associated Protein C; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D003907:Dexamethasone; D015500:Chloramphenicol O-Acetyltransferase; D051497:Receptor, Fibroblast Growth Factor, Type 2; C065104:keratinocyte growth factor receptor