Glucocorticoids are potent regulators of inflammation exerting permissive, stimulatory, and suppressive effects. Glucocorticoid access to intracellular receptors is regulated by the activity of two distinct enzymes known as 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) Type 1 and Type 2, which catalyze the activation or deactivation of glucocorticoids. Although expression of these enzymes in major organ systems and their roles in the metabolic effects of glucocorticoids have been described, their role in the inflammatory response has only recently started to be addressed. In this report, we have studied the expression and activity of 11 beta HSD Type 1 and Type 2 in microglia cells. Microglia, the brain's resident macrophages, initiate and orchestrate CNS inflammatory responses. Importantly, activated microglia are implicated in most neurodegenerative conditions, making them key subjects of study. We found that microglia expressed 11 beta HSD-1, but not 11 beta HSD-2, both in ex vivo FACS-sorted adult cells and in vitro primary cultures. 11 beta HSD-1 expression was increased in LPS-activated microglia. Moreover, 11 beta HSD-1 catalyzed the metabolic conversion of 11-dehydro-corticosterone into corticosterone (CORT), which potently reduced cytokine production in activated microglia. We propose that 11 beta HSD-1 may provide microglia with an intrinsic mechanism to autoregulate and inhibit proinflammatory mediator production through CORT formation.
11 beta-hydroxysteroid dehydrogenase (11 beta HSD) has both dehydrogenase (11 beta DH) and reductase (11 beta R) activities, which catalyse the interconversion of cortisol and cortisone, and prednisolone and prednisone. This enzyme confers specificity on the mineralocorticoid receptor by local oxidation of cortisol to cortisone. Using radiolabelled cortisol 11 beta HSD activity has been shown to be lower in some cases of essential hypertension. This study investigated a novel approach to estimating 11 beta HSD activity in vivo. Plasma steroid kinetics were investigated following oral hydrocortisone (a substrate for 11 beta DH) and prednisone (a substrate for 11 beta R) in five normotensive volunteers after dexamethasone suppression of endogenous steroid production. This approach was evaluated by inducing partial deficiency of 11 beta HSD in the volunteers who took liquorice (to inhibit 11 beta DH) and then carbenoxolone (to inhibit both 11 beta DH and 11 beta R). The ratio of cortisol to prednisolone (formed from prednisone) provided a measure of the activity of both 11 beta DH and 11 beta R. At 75 min after the steroid bolus the ratio increased from (-) (median, range) under control conditions to (-) after liquorice (P = , n = 5), and (-) after carbenoxolone (P = , n = 5). It may therefore be applied to the measurement of 11 beta HSD activity in vivo in large numbers of hypertensive patients without the use of radioisotopes.
This database of proximal tubule (PT) transcripts is based on Affymetrix microarray profiling ( Yu et al. ) carried out in the Epithelial Systems Biology Laboratory, NHLBI. Data are from PT cells freshly isolated from rat kidneys. Signal intensity of all transcripts has been normalized such that the median value is 1. Transcripts with signal values above background () were considered to be expressed. Values are corrected for cross contamination of samples ( non-PT fraction). These experimental data are derived from 3 pairs of Rat 230 Expression Array by Affymetrix Inc.
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