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Inflammatory mediators down-regulate 11beta-hydroxysteroid dehydrogenase type 2 in a human lung epithelial cell line BEAS-2B and the rat lung.

Satoshi Suzuki·Hiroyoshi Tsubochi·Hironori Ishibashi·Yasushi Matsuda·Takashi Suzuki·Zygmunt S Krozowski·Hironobu Sasano·Takashi Kondo
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Abstract

In the lung, anti-inflammatory actions of glucocorticoids would be determined by 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), the microsomal enzyme responsible for the breakdown of bio-active glucocorticoids. However, regulation of 11beta-HSD2 under inflammatory conditions such as acute lung injury is not well understood. In the present study, we examined whether inflammatory substances would influence the activity and mRNA expression of 11beta-HSD2 in the lung. In a human bronchial epithelial cell line BEAS-2B, endotoxin inhibited 11beta-HSD2 enzyme activity in a dose-dependent manner over 48 h with a significant decrease in the mRNA expression. Likewise, tumor necrosis factor (TNF)-alpha inhibited both activity and mRNA expression of 11beta-HSD2. The TNF-alpha-dependent decrease in the enzyme activity was completely blocked by anti-TNF-alpha antibody, while antibody alone showed no significant influence on the enzyme activity. An nitric oxide donor (NO) sodium nitropusside or a cGMP analog 8-br-cGMP caused moderate but significant decreases in both activity and mRNA expression of 11beta-HSD2. Importantly, treatment of rats with endotoxin significantly decreased both activity and mRNA expression of 11beta-HSD2 in the lung tissue. We conclude that lung inflammation reduces local glucocorticoid breakdown and augments glucocorticoid action in the lung by down-regulating 11beta-HSD2 via multiple mechanisms.

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11-beta-Hydroxysteroid DehydrogenasesAnimalsCell LineDown-RegulationEpithelial CellsGene Expression Regulation, EnzymologicHumansInflammation MediatorsLungMaleRNA, MessengerRatsRats, Sprague-DawleyJournal Article

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Satoshi Suzuki, Hiroyoshi Tsubochi, Hironori Ishibashi, Yasushi Matsuda, Takashi Suzuki, Zygmunt S Krozowski, Hironobu Sasano, Takashi Kondo. 2005. Inflammatory mediators down-regulate 11beta-hydroxysteroid dehydrogenase type 2 in a human lung epithelial cell line BEAS-2B and the rat lung.. https://doi.org/10.1620/tjem.207.293

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PubMed2007

Increased renal expression of aquaporin-3 in rats inhibited type 2 11beta-hydroxysteroid dehydrogenase.

AIMS: To investigate whether the regulation of aquaporin (AQP) channels is altered by inhibition of type 2 11beta-hydroxysteroid dehydrogenase (11betaHSD2). METHODS: Male Sprague-Dawley rats were treated with glycyrrhizic acid (GA, 2 g/l drinking water) for 7 days. The expression of AQP2 and AQP3 was determined in the kidney by immunoblotting and immunohistochemistry. The expression of Gsalpha and type VI adenylyl cyclase, and the activity of adenylyl cyclase were also determined. RESULTS: Following the GA treatment, the expression of 11betaHSD2 was significantly decreased in the kidney. The expression of AQP3 was increased, while that of AQP2 remained unchanged. Plasma renin activity and serum aldosterone levels were decreased. Plasma arginine vasopressin (AVP) levels were comparable between the groups. Neither the forskolin-stimulated cAMP generation nor the expression of Gsalpha and type VI adenylyl cyclase was altered significantly. CONCLUSION: A decreased expression of 11betaHSD2 may result in an upregulation of AQP3, in which AVP/cAMP-dependent mechanisms are unlikely to be involved.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2006

Lack of Association of the 11beta-hydroxysteroid dehydrogenase type 1 gene 83,557insA and hexose-6-phosphate dehydrogenase gene R453Q polymorphisms with body composition, adrenal androgen production, blood pressure, glucose metabolism, and dementia.

CONTEXT: Recently, it was proposed that a combination of the 83,557insA polymorphism in the 11beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) gene and the R453Q polymorphism in the hexose-6-phosphate dehydrogenase (H6PD) gene interacts to cause cortisone reductase deficiency (CRD) when at least three alleles are affected. OBJECTIVE: The aim was to study the separate and combined effects of these polymorphisms on body composition, adrenal androgen production, blood pressure, glucose metabolism, and the incidence of dementia in the healthy elderly population. DESIGN/SETTING/PARTICIPANTS: The Rotterdam study (n = 6105) and the Frail Old Men study (n = 347) are population-based cohort studies in the elderly. MAIN OUTCOME MEASURES: Genotype distributions and influences of (combined) genotypes on body mass index, adrenal androgen production, waist to hip ratio, systolic and diastolic blood pressure, fasting glucose levels, glucose tolerance test, and incidence of dementia were measured. RESULTS: No influence of the HSD11B1 83,557insA (allele frequencies 22.0 and 21.5%) and H6PD R453Q (allele frequencies 22.9 and 20.2%) variants was found for the different outcome measures that were investigated, either separately or when at least three alleles were affected. CONCLUSIONS: Two population-based studies among Caucasian elderly showed no evidence for (combined) effects of two polymorphisms in the HSD11B1 and H6PD genes on body composition, adrenal androgen production, blood pressure, glucose metabolism, and incidence of dementia. Moreover, the high frequencies observed for these two polymorphisms do not correspond to the low incidence of CRD observed in the general population. Altogether, it is unlikely that these polymorphisms cause CRD.

11-beta-Hydroxysteroid Dehydrogenases↗