title: The expression of 11 beta-hydroxysteroid dehydrogenase type I by lymphocytes provides a novel means for intracrine regulation of glucocorticoid activities.
abstract: The 11beta-hydroxysteroid dehydrogenase (11beta-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 11beta-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 11beta-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 11beta-HSD1 activity, as did their polarization into Th1 or Th2 cells. CD4(+) T cells isolated from aged donors (>16 mo) had increased 11beta-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-7Ralpha and GCS-induced leucine zipper gene expression. The presence of a functional 11beta-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 11beta-HSD1 provides an additional means to facilitate GCS influences over lymphocyte activities, uncoupled from the plasma concentration of GCS.
authors.affiliation: Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors.forename: Tian Y
authors.initials: TY
authors.lastname: Zhang
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Ding
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Daynes
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D000375:Aging / Q000276:immunology / Q000378:metabolism; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D005938:Glucocorticoids / Q000096:biosynthesis / Q000378:metabolism*; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010088:Oxidoreductases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000378:metabolism / Q000502:physiology; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
chemical_list: D005938:Glucocorticoids; D008024:Ligands; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D011965:Receptors, Glucocorticoid; D010088:Oxidoreductases; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1