11β-Hydroxysteroid Dehydrogenase Type 1 Is Induced in Human Monocytes upon Differentiation to Macrophages

Abstract

11β-hydroxysteroid dehydrogenases (11β-HSD) perform prereceptor metabolism of glucocorticoids through interconversion of the active glucocorticoid, cortisol, with inactive cortisone. Although the immunosuppressive and anti-inflammatory activities of glucocorticoids are well documented, the expression of 11β-HSD enzymes in immune cells is not well understood. Here we demonstrate that 11β-HSD1, which converts cortisone to cortisol, is expressed only upon differentiation of human monocytes to macrophages. 11β-HSD1 expression is concomitant with the emergence of peroxisome proliferator activating receptor γ, which was used as a surrogate marker of monocyte differentiation. The type 2 enzyme, 11β-HSD2, which converts cortisol to cortisone, was not detectable in either monocytes or cultured macrophages. Incubation of monocytes with IL-4 or IL-13 induced 11β-HSD1 activity by up to 10-fold. IFN-γ, a known functional antagonist of IL-4 and IL-13, suppressed the induction of 11β-HSD1 by these cytokines. THP-1 cells, a human macrophage-like cell line, expressed 11β-HSD1 and low levels of 11β-HSD2. The expression of 11β-HSD1 in these cells is up-regulated 4-fold by LPS. In summary, we have shown strong expression of 11β-HSD1 in cultured human macrophages and THP-1 cells. The presence of the enzyme in these cells suggests that it may play a role in regulating the immune function of these cells.

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

“…This is consistent with a recent abstract reporting no detectable 11β-HSD1 activity in human Mφ polarised to Mφ2 by M-CSF, whereas those polarised to Mφ1 (with GM-CSF) showed both 11β-HSD1 activity and 42-fold higher 11β-HSD1 mRNA levels than Mφ2 (Joganathan et al, 2008). It is also consistent with data from the monocyte/Mφ like cell lines THP-1 and J774.1 in which LPS treatment increased expression of 11β-HSD1 Thieringer et al, 2001). These findings suggest that 11β-HSD1 is weakly expressed in resident Mφ, but is induced following exposure to proinflammatory stimuli.…”

“…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 .…”

Glucocorticoids and Cardiovascular Disease

“…We have described 11b-HSD1 in vascular smooth muscle and 11b-HSD2 in the endothelium (67,68), although this distribution may vary somewhat between species and between vascular sites ((69, 70), reviewed in (16)). Low levels of 11b-HSD1 and 11b-HSD2 have also been reported in rat and human heart (67,(71)(72)(73)(74)(75) and 11b-HSD1 is expressed in differentiated macrophages (76,77). On the balance of the evidence, with reference to the model in There have also been sporadic reports that vascular tissue and myocardium express the enzymes necessary for de novo steroidogenesis from cholesterol (72,78,79), although the magnitude, if any, of this contribution appears to be very small.…”

Enhanced Hippocampal Long-Term Potentiation and Spatial Learning in Aged 11β-Hydroxysteroid Dehydrogenase Type 1 Knock-Out Mice

“…Whereas our C57BL/6J mice did not develop metabolic dysfunction with aging on chow diet, so the metabolic protection afforded by 11␤-HSD1 deficiency appears moot, the enzyme is also expressed in inflammatory cells such as the macrophage (Thieringer et al, 2001). Indeed, 11␤-HSD1 Ϫ/Ϫ mice clear acute inflammation more slowly Gilmour et al, 2006).…”