Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2008) 15 OC30

SFEBES2008 Oral Communications Pituitary, disease (8 abstracts)

Local cortisol generation by human macrophage subsets by 11β-hydroxysteroid dehydrogenase type 1 enzyme and its role in ocular immune privilege

Varajini Joganathan 1 , Ahmed Al-Hakami 2 , Saaeha Rauz 2 , Paul M Stewart 1 , Graham R Wallace 2 & Iwona J Bujalska 1

Divisions of 1Medical Sciences and 2Immunity and Infection, University of Birmingham, Birmingham, UK.

The eye is an organ vulnerable to a variety of external and internal stimuli that can abolish its vital function to allow accurate vision of images for survival. Inflammation is the key mediator of immune protection but its consequence leads to the disruption of the visual axis integrity. Due to this precise reason, through adaptation and evolution, the eye has developed mechanisms of immune tolerance and privilege. Glucocorticoids have potent immunosuppressive and anti-inflammatory properties and can be locally produced from circulating inactive cortisone by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). The aim of this study was to demonstrate cortisol generating capacity by human macrophage subsets and elucidate a potential contribution as a mechanism contributing to ocular immune privilege. We investigated the effects of ocular immunosuppressive components – transforming growth factor beta isoform 2 (TGF-β2), alpha melanocyte stimulating hormone (α-MSH) and vasoactive intestinal peptide (VIP) on 11β-HSD1 expression and activity. CD14+ positive cells were isolated from human peripheral blood monocytes using MACS technique and cultured with cytokines GM-CSF or M-CSF allowing differentiation into Mφ1 (inflammatory) and Mφ2 (resident) macrophages respectively. Cultures with ocular immunosuppressive components and their effect on 11β-HSD1 activity and mRNA levels were defined. Mφ1 inflammatory macrophages showed significant 11β-HSD1 oxo-reductase activity (cortisol generation) (19.9±0.9%conversion/105 cells, mean±S.D., n=4) versus zero activity in Mφ2 cells, paralleled with increased mRNA (42-fold). Moreover, H6PDH and interleukin-6 mRNA levels were higher in Mφ1 macrophages (2-fold and 7-fold, respectively). Mφ1 and Mφ2 macrophages express similar levels of glucocorticoid receptor and both have undetectable levels of 11β-HSD2. Immunosuppressive components VIP, TGF-β2 and α-MSH did not alter 11β-HSD1 activity or expression. We conclude that an increase in local cortisol production secondary to up regulation of 11β-HSD1 enzyme following pathogenic stimuli to the eye can be a contributing factor in ocular immune privilege.

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