CD40 brings the shuttle down

Comment on Freeman et al, page 2042

Human immature dendritic cells express the enzyme 11β-HSD1, which regulates the conversion of inactive cortisone into active cortisol, thereby providing an active contribution to the inhibition of DC maturation.

Glucocorticoids (GCs) have important inflammatory and immunosuppressive properties and are widely used clinically. Many cell types, including T cells, macrophages, and dendritic cells (DCs), are targets of GCs. Functional maturation of DCs has been recognized as one of the critical events in immune regulation, a process that seems to be very tightly controlled. Proinflammatory signals such as cytokines, triggering of Toll-like receptors (TLRs), or cognate interaction with CD40 ligand (CD40L)–expressing T cells leads to maturation of DCs. In contrast, anti-inflammatory agents, as well as immunosuppressive drugs such as GCs, can inhibit this maturation process.¹ 

Like exogenously administered GCs, endogenous GCs play an important physiologic role. Endogenous GCs exist in 2 different forms, the active 11-hydroxy (cortisol) form and the inactive 11-keto (cortisone) form. Regulation of endogenous GC activity is finetuned by an intracellular conversion through the enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD). Whereas the type-2 form of this enzyme (highly expressed in kidney and fetus) can inactivate cortisol via dehydrogenation, the type-1 enzyme has reductase activity and generates cortisol from cortisone. This process is also known as the cortisol-cortisone shuttle.²  Both cortisol and cortisone are normally present in serum in concentrations ranging from 10^-7 to 10^-9 M, mostly with cortisone in excess. In this issue of Blood, Freeman and colleagues show that immature DCs express the enzyme 11β-HSD1, thereby controlling the intracellular conversion of the inactive cortisone into the active hormone cortisol.FIG1 

The first important finding of this study is the specific expression of 11β-HSD1, but not 11β-HSD2, when DCs develop in vitro from monocytes. Of importance, this expression is shown not only at the mRNA and protein levels, but also by a direct measurement of the enzyme activity. Adding physiologic concentrations of inactive cortisone to DC cultures inhibits DC activation through local generation of cortisol, an effect that can be prevented by an 11β-HSD inhibitor, suggesting that immature monocyte-derived DCs are biased toward maintenance of the immature state. Recently, expression of 11β-HSD was also demonstrated in murine bone marrow–derived DCs.³  One limitation of these studies is that most results are based on in vitro–generated DCs. It will be important to confirm these results in freshly isolated DCs. Furthermore, in view of their different functional capacities, it will be interesting to investigate the relevance of this enzyme shuttle in other DC subsets. Langerhans cell function and development from CD34 precursors are not hampered by exposure to GCs,⁴  demonstrating that not all DC subsets are equally sensitive to inhibition by GCs.

Data provided already predict that it could be advantageous for maturing DCs to down-regulate the cortisol shuttle. Freeman and colleagues investigated the effect of DC maturation on the expression and function of 11β-HSD and found that different modes of maturation showed differential effects on 11β-HSD. Maturation induced by CD40L activation, as a mimic of T-cell–mediated signals, resulted in a strong decrease in 11β-HSD activity. However, this decrease in activity was not observed at the protein or mRNA level. The molecular mechanism of this reduced activity is not clear at present. In contrast, the authors observed that innate maturation induced by tumor necrosis factor α (TNF-α)or a panel of different TLR ligands, including zymosan (TLR2), lipopolysaccharide (LPS, TLR4), polyinosine:polycytidylic acid (poly I:C, TLR3), and flagellin (TLR5), showed no effect or even a slight enhancement of 11β-HSD activity, suggesting that especially CD40L-matured DCs actively prevent the generation of endogenous GCs. This result adds important information to recent findings that different modes of DC maturation result in different stages of maturation.⁵  It will be a major challenge in the near future to determine the contribution of the endogenous regulation of hormone availability for DC function during different stages of maturation. ▪