Ontogeny of 11β-Hydroxysteroid Dehydrogenase: Activity in the Placenta, Kidney, Colon of Fetal Rats and Rabbits

Hundertmark, S.; Bühler, H.; Fromm, Michael; Kruner-Gareis, B; Kruner, M; Ragosch,; Kuhlmann, K.; Seckl,

doi:10.1055/s-2001-12429

Cited by 19 publications

(13 citation statements)

References 28 publications

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“…The recent report of 11b HSD 1's role in fetal lung development by Hundertmark [1,2] has confirmed our earlier findings using contemporary techniques. The observation that knocking out the 11b HSD 1 gene gives a lung phenotype consistent with its role in fetal lung maturation and pulmonary surfactant production [3] is further confirmation of the earlier series of studies of its role in this critical process of fetal transition and viability cited in this commentary.…”

supporting

confidence: 81%

“…

Hundertmark et al [1] recently reported that 11-oxo steroids, like their 11-hydroxy isoforms, can stimulate fetal lung maturation due to the expression of 11b-hydroxysteroid dehydrogenase Type 1 (11b HSD 1), the enzyme that converts (inactive) cortisone to (active) cortisol [2]. In a subsequent study, this group has shown that knocking out the 11b HSD 1 gene inhibits lung maturation and surfactant synthesis [3], confirming the biological significance of 11b HSD 1 in lung development.

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confidence: 99%

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The Physiologic Significance of 11beta-hydroxysteroid Dehydrogenase Type 1 in Fetal Lung Development Redux

Torday

2005

Horm Metab Res

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Hundertmark et al. [1] recently reported that 11-oxo steroids, like their 11-hydroxy isoforms, can stimulate fetal lung maturation due to the expression of 11b-hydroxysteroid dehydrogenase Type 1 (11b HSD 1), the enzyme that converts (inactive) cortisone to (active) cortisol [2]. In a subsequent study, this group has shown that knocking out the 11b HSD 1 gene inhibits lung maturation and surfactant synthesis [3], confirming the biological significance of 11b HSD 1 in lung development. A series of studies performed by my collaborators and myself beginning more than 30 years ago had previously demonstrated the biological activity and significance of 11b HSD 1 in fetal human, rabbit and rat lung development. These studies were the first to elucidate the physiologic role of glucocorticoids in normal fetal lung development [4]. I would like to relate these studies, which were overlooked in the Hundertmark publications.Our laboratory at McGill University was the first to discover why the placenta is a`barrier' to steroids. Hillman and Giroud [5] demonstrated that the placenta quantitatively oxidizes cortisol to cortisone as it passes through from mother to fetus. This was thought to be protective since glucocorticoids are classically considered to be catabolic. By contrast, Burton demonstrated that fetal mouse liver had the capacity to convert 11-dehydrocorticosterone to corticosterone [6,7], setting a precedent for the local tissue activation of glucocorticoids in specific fetal tissues. The discovery by Liggins that glucocorticoids stimulate fetal lung development and reduce the morbidity and mortality of preterm birth catalyzed the then burgeoning interest in fetal steroid metabolism [8]. The presence of 11b HSD 1 activity in human fetal lung cells was first reported by Smith, Torday and Giroud in 1973 [9]. In a subsequent study [10], we showed that cortisol could directly affect fetal rabbit lung cell surfactant phospholipid synthesis, and that cortisol stimulated 11b HSD 1 activity by fetal rabbit lung cells [11]. To determine whether 11b HSD 1 could actively generate cortisol from cortisone in the intact fetal lung, we perfused fetal rabbit lung via the pulmonary artery with 3 H-cortisone, and demonstrated quantitative secretion of 3 H-cortisol from the pulmonary vein [12]; we also reported that 11b HSD 1 activity increased significantly from 23 to 29 days gestation (day 31 = term).The physiological significance of 11b HSD 1 activation by fetal lung fibroblasts was elucidated by in-depth studies on the cellmolecular mechanism of glucocorticoid action on lung maturation. Smith [13] discovered that cortisol stimulated lung fibroblast synthesis of a low molecular-weight paracrine factor he termed fibroblast-pneumonocyte factor (FPF), which was secreted into the extracellular milieu and stimulated surfactant phospholipid synthesis by the alveolar type II cell [14]. My laboratory pursued these observations by demonstrating that the hormonedependent sex difference in fetal lung development was due to the differential ...

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confidence: 99%

The Physiologic Significance of 11beta-hydroxysteroid Dehydrogenase Type 1 in Fetal Lung Development Redux

Torday

2005

Horm Metab Res

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“…The capacity of thymocytes to generate bioactive GCS may be especially important during fetal development, when placental and fetal tissue 11␤-HSD2 is functioning to inactivate maternal GCS, preventing any deleterious effects of bioactive GCS on the developing fetus (21,22,76). The 11-keto GCS-rich environment present throughout most of gestation would maximize the potential for thymocyte 11␤-HSD1 activities.…”

Section: Discussionmentioning

confidence: 99%

The Expression of 11β-Hydroxysteroid Dehydrogenase Type I by Lymphocytes Provides a Novel Means for Intracrine Regulation of Glucocorticoid Activities

Zhang

Ding

Daynes

2005

The Journal of Immunology

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The 11β-hydroxysteroid dehydrogenase (11β-HSD) enzymes control the interconversion of active glucocorticoids (GCS) and their inactive 11-keto metabolites, a process commonly referred to as the cortisone/cortisol shuttle. Although the prereceptor metabolism of GCS by 11β-HSD is well documented in a variety of cells and tissues, it has not yet been carefully investigated in the major cell types of the immune system. In this study, we demonstrate that 11β-HSD1 transcripts, protein, and enzyme activities are actively expressed in murine CD4+, CD8+, and B220+ lymphocytes, as well as CD11c+ dendritic cells. Only reductase activity was observed in living cells, evidenced by the restricted conversion of cortisone to cortisol. Activation of CD4+ T cells increased their 11β-HSD1 activity, as did their polarization into Th1 or Th2 cells. CD4+ T cells isolated from aged donors (>16 mo) had increased 11β-HSD1 protein and an elevated capacity to convert cortisone to cortisol. The GCS generated in murine CD4+ T cells from their inactive 11-keto metabolites could activate the GCS receptor, demonstrated by an up-regulation of IL-7Rα and GCS-induced leucine zipper gene expression. The presence of a functional 11β-HSD1 provides lymphocytes with a novel intracrine regulatory mechanism that could influence such processes as lymphocyte development, effector function, and susceptibility to apoptosis. Thus, the presence of 11β-HSD1 provides an additional means to facilitate GCS influences over lymphocyte activities, uncoupled from the plasma concentration of GCS.

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“…In early to mid gestation, 11␤-HSD2 is found throughout the kidney in the mouse (93), sheep (385), and human (285,673), notably in Bowman's capsule and the vascular tufts of the developing glomeruli as they migrate from the surface to the inner cortex (126). In late gestation, the expression pattern becomes more discrete with very high levels in the distal convoluted tubules and collecting ducts (93,126,127,307), resembling the adult pattern. Indeed, in the later stages of gestation, MR becomes colocalized with 11␤-HSD2, suggesting 11␤-HSD2 is protecting inappropriate activation of MR at this time, whereas at earlier time points 11␤-HSD2 may modulate glucocorticoid signaling through GR (93, 126).…”

Section: Fetal Kidneymentioning

confidence: 99%

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

Chapman

Holmes

Seckl

2013

Physiological Reviews

707

601

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Glucocorticoid action on target tissues is determined by the density of “nuclear” receptors and intracellular metabolism by the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) which catalyze interconversion of active cortisol and corticosterone with inert cortisone and 11-dehydrocorticosterone. 11β-HSD type 1, a predominant reductase in most intact cells, catalyzes the regeneration of active glucocorticoids, thus amplifying cellular action. 11β-HSD1 is widely expressed in liver, adipose tissue, muscle, pancreatic islets, adult brain, inflammatory cells, and gonads. 11β-HSD1 is selectively elevated in adipose tissue in obesity where it contributes to metabolic complications. Similarly, 11β-HSD1 is elevated in the ageing brain where it exacerbates glucocorticoid-associated cognitive decline. Deficiency or selective inhibition of 11β-HSD1 improves multiple metabolic syndrome parameters in rodent models and human clinical trials and similarly improves cognitive function with ageing. The efficacy of inhibitors in human therapy remains unclear. 11β-HSD2 is a high-affinity dehydrogenase that inactivates glucocorticoids. In the distal nephron, 11β-HSD2 ensures that only aldosterone is an agonist at mineralocorticoid receptors (MR). 11β-HSD2 inhibition or genetic deficiency causes apparent mineralocorticoid excess and hypertension due to inappropriate glucocorticoid activation of renal MR. The placenta and fetus also highly express 11β-HSD2 which, by inactivating glucocorticoids, prevents premature maturation of fetal tissues and consequent developmental “programming.” The role of 11β-HSD2 as a marker of programming is being explored. The 11β-HSDs thus illuminate the emerging biology of intracrine control, afford important insights into human pathogenesis, and offer new tissue-restricted therapeutic avenues.

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Ontogeny of 11β-Hydroxysteroid Dehydrogenase: Activity in the Placenta, Kidney, Colon of Fetal Rats and Rabbits

Cited by 19 publications

References 28 publications

The Physiologic Significance of 11beta-hydroxysteroid Dehydrogenase Type 1 in Fetal Lung Development Redux

The Physiologic Significance of 11beta-hydroxysteroid Dehydrogenase Type 1 in Fetal Lung Development Redux

The Expression of 11β-Hydroxysteroid Dehydrogenase Type I by Lymphocytes Provides a Novel Means for Intracrine Regulation of Glucocorticoid Activities

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

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