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-Hydroxysteroid Dehydrogenase Type I by Lymphocytes Provides a Novel Means for Intracrine Regulation of Glucocorticoid Activities1
* Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132; and
Geriatric Research, Education and Clinical Center, Veterans Affairs Medical Center, Salt Lake City, UT 84112
The 11
-hydroxysteroid dehydrogenase (11-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 11-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 11-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 11-HSD1 activity, as did their polarization into Th1 or Th2 cells. CD4+ T cells isolated from aged donors (>16 mo) had increased 11-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-7R
and GCS-induced leucine zipper gene expression. The presence of a functional 11-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 11-HSD1 provides an additional means to facilitate GCS influences over lymphocyte activities, uncoupled from the plasma concentration of GCS.
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