title: Lymphoid organs of neonatal and adult mice preferentially produce active glucocorticoids from metabolites, not precursors.
abstract: Glucocorticoids (GCs) are circulating adrenal steroid hormones that coordinate physiology, especially the counter-regulatory response to stressors. While systemic GCs are often considered immunosuppressive, GCs in the thymus play a critical role in antigen-specific immunity by ensuring the selection of competent T cells. Elevated thymus-specific GC levels are thought to occur by local synthesis, but the mechanism of such tissue-specific GC production remains unknown. Here, we found metyrapone-blockable GC production in neonatal and adult bone marrow, spleen, and thymus of C57BL/6 mice. This production was primarily via regeneration of adrenal metabolites, rather than de novo synthesis from cholesterol, as we found high levels of gene expression and activity of the GC-regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), but not the GC-synthetic enzyme CYP11B1. Furthermore, incubation with physiological concentrations of GC metabolites (11-dehydrocorticosterone, prednisone) induced 11β-HSD1- and GC receptor-dependent apoptosis (caspase activation) in both T and B cells, showing the functional relevance of local GC regeneration in lymphocyte GC signaling. Local GC production in bone marrow and spleen raises the possibility that GCs play a key role in B cell selection similar to their role in T cell selection. Our results also indicate that local GC production may amplify changes in adrenal GC signaling, rather than buffering against such changes, in the immune system.
authors.affiliation: Department of Psychology, University of British Columbia, 2136 West Mall, Vancouver V6T 1Z4, Canada; Department of Zoology, University of British Columbia, 4200-6270 University Blvd, Vancouver V6T 1Z4, Canada. Electronic address: taves@zoology.ubc.ca.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Taves
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, 1365-2350 Health Sciences Mall, Vancouver V6T 1Z3, Canada. Electronic address: aplumb@mail.ubc.ca.
authors.forename: Adam W
authors.initials: AW
authors.lastname: Plumb
authors.affiliation: Department of Psychology, University of British Columbia, 2136 West Mall, Vancouver V6T 1Z4, Canada. Electronic address: anastasiakorol@hotmail.ca.
authors.forename: Anastasia M
authors.initials: AM
authors.lastname: Korol
authors.affiliation: Department of Laboratory Medicine, St Paul's Hospital, 1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada. Electronic address: gvandergugten@providencehealth.bc.ca.
authors.forename: Jessica Grace
authors.initials: JG
authors.lastname: Van Der Gugten
authors.affiliation: Department of Laboratory Medicine, St Paul's Hospital, 1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada. Electronic address: dtholmes@providencehealth.bc.ca.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Holmes
authors.affiliation: Department of Zoology, University of British Columbia, 4200-6270 University Blvd, Vancouver V6T 1Z4, Canada; Department of Microbiology and Immunology, University of British Columbia, 1365-2350 Health Sciences Mall, Vancouver V6T 1Z3, Canada. Electronic address: ninan@mail.ubc.ca.
authors.forename: Ninan
authors.initials: N
authors.lastname: Abraham
authors.affiliation: Department of Psychology, University of British Columbia, 2136 West Mall, Vancouver V6T 1Z4, Canada; Department of Zoology, University of British Columbia, 4200-6270 University Blvd, Vancouver V6T 1Z4, Canada; Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada. Electronic address: ksoma@psych.ubc.ca.
authors.forename: Kiran K
authors.initials: KK
authors.lastname: Soma
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001853:Bone Marrow / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism*; D013252:Steroid 11-beta-Hydroxylase / Q000378:metabolism*; D013950:Thymus Gland / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D013252:Steroid 11-beta-Hydroxylase
keywords: 11beta-Hydroxysteroid dehydrogenase; Apoptosis; Carbenoxolone; Cytochrome P450 11B1; Glucocorticoid receptor; Immunosteroid; Lymphocyte; Metyrapone; Prednisone; Stress