The Expression of 11β-Hydroxysteroid Dehydrogenase Type I by Lymphocytes Provides a Novel Means for Intracrine Regulation of Glucocorticoid Activities

Abstract

The 11β-hydroxysteroid dehydrogenase (11β-HSD) enzymes control the interconversion of active glucocorticoids (GCS) and their inactive 11-keto metabolites, a process commonly referred to as the cortisone/cortisol shuttle. Although the prereceptor metabolism of GCS by 11β-HSD is well documented in a variety of cells and tissues, it has not yet been carefully investigated in the major cell types of the immune system. In this study, we demonstrate that 11β-HSD1 transcripts, protein, and enzyme activities are actively expressed in murine CD4+, CD8+, and B220+ lymphocytes, as well as CD11c+ dendritic cells. Only reductase activity was observed in living cells, evidenced by the restricted conversion of cortisone to cortisol. Activation of CD4+ T cells increased their 11β-HSD1 activity, as did their polarization into Th1 or Th2 cells. CD4+ T cells isolated from aged donors (>16 mo) had increased 11β-HSD1 protein and an elevated capacity to convert cortisone to cortisol. The GCS generated in murine CD4+ T cells from their inactive 11-keto metabolites could activate the GCS receptor, demonstrated by an up-regulation of IL-7Rα and GCS-induced leucine zipper gene expression. The presence of a functional 11β-HSD1 provides lymphocytes with a novel intracrine regulatory mechanism that could influence such processes as lymphocyte development, effector function, and susceptibility to apoptosis. Thus, the presence of 11β-HSD1 provides an additional means to facilitate GCS influences over lymphocyte activities, uncoupled from the plasma concentration of GCS.

Local Amplification of Glucocorticoids by 11β-Hydroxysteroid Dehydrogenase Type 1 Promotes Macrophage Phagocytosis of Apoptotic Leukocytes

“…The lower 11␤-HSD1 activity in other blood cell types, including lymphocytes (25), suggests that macrophages are uniquely well placed to exploit the significant pool of intrinsically inactive 11-keto metabolites that circulate at levels equivalent to or exceeding basal free corticosterone or cortisol (26). The anti-inflammatory actions of 11-dehydrocorticosterone are evidenced by its equipotency with corticosterone in the ability to increase macrophage phagocytosis in vitro, dependent upon Hsd11b1 expression.…”

Obesity and corticosteroids: 11β-Hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease

“…The role and effect of 11 -HSD1 inhibition of macrophage function in adipose and atherosclerotic lesions is unclear. Equally, lymphocyte and other immunocytes express 11 -HSD1 (Daynes et al, 2005). Determining the role of 11 -HSD1 in these cells is critical to the application of inhibitors and may present unwanted adverse effects during acute infection or acute-or severe/chronic-inflammation .…”

Characterisation of the prereceptor regulation of glucocorticoids in the anterior segment of the rabbit eye

“…It is possible that selective 11b-HSD1 inhibitors may improve epithelial stability in eyes vulnerable to epithelial defects. Furthermore, as 11b-HSD1 is potently regulated by cytokines and active GC is a key component of immune regulation (Thieringer et al 2001, Freeman et al 2005, Zhang et al 2005, the expression of this isozyme in the conjunctival and corneal epithelia and the autocrine regulation of cortisol may be an integral feature of the ocular surface protective barrier. Further studies are now necessary to tease apart the exact role of 11b-HSD1 in ocular surface renewal, protection and immune regulation.…”

“…In vivo oxo-reductase activity (cortisone/ cortisol) predominates through the provision of cofactor (NADPH) by hexose-6-phosphate dehydrogenase, thereby mediating classical GC responses (Draper et al 2003, Bujalska et al 2005. Interest in the isozyme has escalated primarily because of its putative role in diseases such as human obesity, insulin resistance and osteoporosis (Kotelevtsev et al 1997, Tomlinson et al 2000, Bujalska et al 2002 and also its role in the regulation of immune-cell function and inflammation (Thieringer et al 2001, Freeman et al 2005, Zhang et al 2005. A second dehydrogenase isozyme (11b-HSD2) protects the mineralocorticoid receptor (MR) from cortisol excess by inactivating it to cortisone (Funder et al 1988).…”