The expression of 11β-hydroxysteroid dehydrogenase type I by lymphocytes provides a novel means for intracrine regulation of glucocorticoid activities

TY Zhang, X Ding, RA Daynes - The Journal of Immunology, 2005 - journals.aai.org
TY Zhang, X Ding, RA Daynes
The Journal of Immunology, 2005journals.aai.org
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 …
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.
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