Decreased 11β-hydroxysteroid dehydrogenase 1 in lungs of steroid receptor coactivator (Src)-1/-2 double-deficient fetal mice is caused by impaired glucocorticoid and cytokine signaling

Jingfei Chen, Ritu Mishra, Yaqin Yu, Jeffrey G. McDonald, Kaitlyn M. Eckert, Lu Gao, Carole R. Mendelson

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)16243-16261
Number of pages19
JournalFASEB Journal
Volume34
Issue number12
DOIs
StatePublished - Dec 2020

Keywords

  • 11β-hydroxysteroid dehydrogenase type 1
  • cytokines
  • fetal lung development
  • glucocorticoids
  • steroid receptor coactivators (SRCs)

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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