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1 Academic Unit of Ophthalmology, Division of Immunity and Infection and
2 Department of Endocrinology, Division of Medical Sciences, Institute of Biomedical Research, The Medical School, University of Birmingham, Edgbaston, Birmingham B15 5TT, UK
(Requests for offprints should be addressed to S Rauz, Birmingham and Midland Eye Centre, Dudley Road, Birmingham B18 7QU, UK; Email: s.rauz{at}bham.ac.uk)
* (E A Walker and S Rauz contributed equally to this work)
The prereceptor regulation of glucocorticoids (GCs) by 11ß-hydroxysteroid dehydrogenase type-1 (11ß-HSD1), a bidirectional isozyme that interconverts active (cortisol) and inactive (cortisone) GCs, is an established determinant of GC function in tissues such as liver, adipose and bone. Although the therapeutic use of GCs is abundant in ophthalmic practice, where GC interactions with nuclear receptors modulate gene transcription, the prereceptor regulation of endogenous cortisol is not well described in ocular tissues. Recent descriptive studies have localised 11ß-HSD1 to the human corneal epithelium and non-pigmented epithelium (NPE) of the ciliary body, indicating a link to corneal epithelial physiology and aqueous humour production. In this study, we characterise the functional aspects of the autocrine regulation of GCs in the anterior segment of the rabbit eye. Using our in-house generated primary antibody to human 11ß-HSD1, immunohistochemical analyses were performed on paraffin-embedded sections of whole New Zealand white albino rabbits, (NZWAR) eyes. As in human studies, 11ß-HSD1 was localised to the corneal epithelium and the NPE. No staining was seen in the albino ‘pigmented’ ciliary epithelium. Specific enzyme assays for oxo-reductase (cortisone
cortisol) and dehydrogenase (cortisolcortisone) activity indicated predominant 11ß-HSD1 oxo-reductase activity from both the intact ciliary body tissue (n=12, median 2.1 pmol/mg per h and range 1.25–2.8 pmol/mg per h; P=0.006) and primary cultures of corneal epithelial cells (n=12, median 3.0 pmol/mg per h and range 1.0–7.4 pmol/mg per h, P=0.008) compared with dehydrogenase activity (median 1.0 pmol/mg per h and range 0.5–2.0 pmol/mg per h; median 0.5 pmol/mg per h and range 0.25–1.9 pmol/mg per h respectively). These findings were supported by expression of 11ß-HSD1 protein as visualised by Western blotting of ciliary body tissue and immunocytochemistry of corneal epithelial cells. Reduction of corneal epithelial cell proliferation was seen after primary cultures were co-incubated with cortisol and cortisone. 11ß-HSD1 activity was not demonstrated in naïve conjunctival fibroblasts or corneal stromal keratocytes. Our results indicate that the distribution of 11ß-HSD1 in the rabbit resembles that of the human eye and activates cortisone to cortisol in both corneal and uveal tissues. The NZWAR provides a suitable in vivo model for the further evaluation of 11ß-HSD1 activity in the eye, especially its role in corneal epithelial and ciliary body physiology.
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  I. J Bujalska, O. M Durrani, J. Abbott, C. U Onyimba, P. Khosla, A. H Moosavi, T. T Q Reuser, P. M Stewart, J. W Tomlinson, E. A Walker, et al. Characterisation of 11{beta}-hydroxysteroid dehydrogenase 1 in human orbital adipose tissue: a comparison with subcutaneous and omental fat J. Endocrinol., February 1, 2007; 192(2): 279 - 288. [Abstract] [Full Text] [PDF]
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