A Putative Role for 11ß-Hydroxysteroid Dehydrogenase 1 in the Regulation of Human Cerebrospinal Fluid Dynamics

Abstract

Purpose:: The prereceptor regulation of glucocorticoids (GC) is mediated by 11ß-hydroxysteroid dehydrogenases (11ß-HSDs). The type 1 isoform is responsible for the generation of active cortisol from cortisone in tissues such as liver and adipose, whereas 11ß-HSD2 regulates sodium and ion transport by abrogating cortisol to inactive cortisone. Recently, we have shown the presence of functional 11ß-HSD1 in the ciliary body of the eye where it may be important in mediating intraocular cortisol, ion transport and intraocular pressure. We propose that a similar mechanism may exist in the embryologically-related epithelium of the choroid plexus (CP), which is responsible for sodium regulation and cerebrospinal fluid (CSF) production in the brain. CSF circulates from the CP through the intracerebral ventricular system, draining predominantly through the arachnoid granulation tissue (AGT). The balance between production and drainage of CSF gives rise in part, to intracranial pressure. The aim of this study was to characterise CP and AGT as GC target tissues.

Methods:: Immunohistochemical analyses were performed on paraffin embedded 5µm sections of human postmortem CP and AGT using in-house generated primary antibody to human 11ß-HSD1 and 2. Specific 11ß-HSD enzyme assays for oxo-reductase (cortisone to cortisol) and dehydrogenase (cortisol to cortisone) activity were conducted on whole tissue CP and AGT explants. Expression of GC target genes were analysed in both whole tissue (CP, AGT) and a primary untransformed human CP epithelial cell line (HCPEpi) by conventional RT-PCR.

Results:: Immunolocalisation studies identified 11ß-HSD1 in the CP epithelium, and AGT endothelium and cap cell cluster. These findings were endorsed by activity studies in CP explants that confirmed predominant oxo-reductase (cortisone to cortisol, 24 ± 11pmol/g/h) versus dehydrogenase (cortisol to cortisone, 3 ± 3 pmol/g/h) activity. No 11ß-HSD activity was detected in the AGT. Key GC target genes (11ß-HSD1, hexose-6-phosphate dehydrogenase, serum and glucocorticoid regulated kinase, GC receptor, mineralocorticoid receptor) were all expressed in CP, AGT and the HCPEpi cell line.

Conclusions:: We have identified a novel cortisol generating system in the CP that may represent an underlying mechanism mediating CSF cortisol and dynamics. 11ß-HSD1 may therefore be important in the regulation of intracranial pressure.

Keywords: corticosteroids • gene/expression • visual impairment: neuro-ophthalmological disease