Expression of 11β-hydroxysteroid dehydrogenase type 1 permits regulation of glucocorticoid bioavailability by human dendritic cells

Abstract

Glucocorticoids (GCs) exert powerful antiinflammatory effects that may relate in part to their ability to restrict the differentiation and function of dendritic cells (DCs). Although these inhibitory effects are dependent upon GCs binding to nuclear glucocorticoid receptors (GRs), fine-tuning of GR signaling is achieved by prereceptor interconversion of cortisol that binds GRs with high affinity and cortisone that does not. We show for the first time that human monocyte-derived DCs are able to generate cortisol as a consequence of up-regulated expression of the enzyme 11␤-hydroxysteroid dehydrogenase type 1 (11␤-HSD1). Immature DCs demonstrate selective enhancement of 11␤-HSD1 reductase activity, leading to increased conversion of inactive cortisone to active cortisol. Enhancement of GC bioavailability is maintained or increased upon terminal differentiation induced by signals associated with innate immune activation. In marked contrast, maturation induced by CD40 ligation leads to a sharp reduction in cortisol generation by DCs. The differentiation of DCs from monocyte precursors is inhibited at physiologic concentrations of inactive cortisone, an effect that requires activity of the 11␤-HSD1 enzyme. In conclusion, prereceptor regulation of endogenous GCs appears to be an important determinant of DC function and represents a potential target for therapeutic manipulation. ( IntroductionSynthetic derivatives of naturally occurring glucocorticoids (GCs) have major anti-inflammatory and immunosuppressive properties that make them suitable for the treatment of autoimmune disease or the prevention of allograft rejection. 1 Rational design of novel synthetic GC derivatives or of strategies that enable their optimal use requires an improved understanding of how exogenous and endogenous GCs exert their effects upon the immune system. Studies in vitro which use GCs at supraphysiologic concentrations suggest that major cellular targets are T cells 2,3 and dendritic cells (DCs). [4][5][6][7][8][9] In the latter case, GCs inhibit in vitro differentiation of DCs from their precursor cells [4][5][6]9 and impair their capacity to undergo terminal differentiation or generate proinflammatory cytokines. [5][6][7][8][9] The role of endogenous GCs in modulating DC development or function however is unknown.Crucial to any concept that seeks to explain how endogenous GCs influence DC development is an appreciation of how GC levels are regulated in vivo. Endogenous GCs exist either as active 11-hydroxy ligands (eg, cortisol) that bind glucocorticoid receptor ␣ (GR␣) or inactive 11-keto derivatives which do not (eg, cortisone). 10,11 Fine-tuning of active GC bioavailability in peripheral tissues is regulated by prereceptor interconversion of inactive and active ligands mediated by 2 isozymes of 11␤-hydroxysteroid dehydrogenase (11␤-HSD) that catalyze the so-called "cortisolcortisone" shuttle. 10,11 Inactivation of cortisol by dehydrogenation to cortisone is mediated by 11␤-HSD2. In the kidney, this activity prevents competition betwee...

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

“…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).…”

The role and regulation of 11β-hydroxysteroid dehydrogenase type 1 in the inflammatory response

“…Circulating mouse white blood cells do not express 11β-HSD2 mRNA ) and 11β-HSD2 mRNA is absent from mouse Mφ , DC , lymphocytes and mast cells (Coutinho et al, manuscript in preparation). Similarly, 11β-HSD2 mRNA is not detected in human blood from normal individuals ) and it is absent or at negligible levels in normal human monocytes (Freeman et al, 2005;Thieringer et al, 2001), Mφ ) and DC (Freeman et al, 2005). However, 11β-HSD2 has been reported in human leukocytes in pathological conditions.…”

“…These findings suggest that 11β-HSD1 is weakly expressed in resident Mφ, but is induced following exposure to proinflammatory stimuli. A different situation may exist with monocytes that encounter the Th2 polarising cytokines, IL-4 and IL-13 which, in common with 1, 25-dihydroxyvitamin D 3 , markedly increased 11β-HSD1 activity in monocytes (Freeman et al, 2005;Thieringer et al, 2001). Incubation of monocytes with TNFα, IL-1 or LPS had no discernable effect .…”

“…Although less well characterised than Mφ, the differentiation of immature DC is similarly influenced by microenvironment, judged by cell surface marker expression, with glucocorticoids having potent effects, for eg modulating appearance of CD1a, a Langerhan's cell marker, on immature dendritic cells (Freeman et al, 2005). Immature DCs have high endocytic activity and low T-cell activation potential.…”

“…Differentiation of human monocytes to immature DC (by incubation with GM-CSF and IL-4) was associated with a marked up-regulation of 11β-HSD1 activity within 2d, peaking at 7d (7pmol cortisol/h/10 6 cells) which was maintained following maturation by innate immune activating signals (TNFα, Toll-like receptor activation) but which decreased following maturation by CD40 ligation, an adaptive immune activation signal (Freeman et al, 2005). The latter decrease in enzyme activity occurred in the absence of alterations in either 11β-HSD1 protein levels or mRNA levels, thus must involve a posttranslational mechanism (Freeman et al, 2005). Collectively, these findings highlight the exquisite dependence of 11β-HSD1 expression and regulation upon cellular differentiation state and the local microenvironment.…”