Decreased 11β‐hydroxysteroid dehydrogenase 1 in lungs of steroid receptor coactivator (Src)‐1/‐2double‐deficient fetal mice is caused by impaired glucocorticoid and cytokine signaling
Autor: | Ritu Mishra, Kaitlyn M. Eckert, Carole R. Mendelson, Yaqin Yu, Lu Gao, Jeffrey G. McDonald, Jingfei Chen |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
medicine.medical_specialty medicine.medical_treatment Biochemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Glucocorticoid receptor 11β-hydroxysteroid dehydrogenase type 1 Corticosterone Internal medicine Genetics medicine Receptor Molecular Biology biology Chemistry Surfactant protein A 030104 developmental biology Cytokine Endocrinology biology.protein hormones hormone substitutes and hormone antagonists 030217 neurology & neurosurgery Glucocorticoid Biotechnology Proto-oncogene tyrosine-protein kinase Src medicine.drug |
Zdroj: | The FASEB Journal. 34:16243-16261 |
ISSN: | 1530-6860 0892-6638 |
Popis: | Our previous research revealed that steroid receptor coactivators (Src)-1 and -2 serve a critical cooperative role in production of parturition signals, surfactant protein A and platelet-activating factor, by the developing mouse fetal lung (MFL). To identify the global landscape of genes in MFL affected by Src-1/-2 double-deficiency, we conducted RNA-seq analysis of lungs from 18.5 days post-coitum (dpc) Src-1-/- /-2-/- (dKO) vs. WT fetuses. One of the genes most highly downregulated (~4.8 fold) in Src-1/-2 dKO fetal lungs encodes 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which catalyzes conversion of inactive 11-dehydrocorticosterone to the glucocorticoid receptor (GR) ligand, corticosterone. Glucocorticoids were reported to upregulate 11β-HSD1 expression in various cell types via induction of C/EBP transcription factors. We observed that C/ebpα and C/ebpβ mRNA and protein were markedly reduced in Src-1/-2 double-deficient (Src-1/-2d/d ) fetal lungs, compared to WT. Moreover, glucocorticoid induction of 11β-hsd1, C/ebpα and C/ebpβ in cultured MFL epithelial cells was prevented by the SRC family inhibitor, SI-2. Cytokines also contribute to the induction of 11β-HSD1. Expression of IL-1β and TNFα, which dramatically increased toward term in lungs of WT fetuses, was markedly reduced in Src-1/-2d/d fetal lungs. Our collective findings suggest that impaired lung development and surfactant synthesis in Src-1/-2d/d fetuses are likely caused, in part, by decreased GR and cytokine induction of C/EBP and NF-κB transcription factors. This results in reduced 11β-HSD1 expression and glucocorticoid signaling within the fetal lung, causing a break in the glucocorticoid-induced positive feedforward loop. |
Databáze: | OpenAIRE |
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