Lymphoid organs of neonatal and adult mice preferentially produce active glucocorticoids from metabolites, not precursors

May 12, 2016Brain, behavior, and immunity

Lymphoid organs in newborn and adult mice mainly create active glucocorticoids from metabolites rather than from precursors

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Abstract

Mice exhibit metyrapone-blockable glucocorticoid production in bone marrow, spleen, and thymus.

Local glucocorticoid production is primarily through the regeneration of adrenal metabolites.
High levels of gene expression and activity were found for the enzyme that regenerates glucocorticoids, while the enzyme responsible for their synthesis from cholesterol was not active.
Incubation with specific glucocorticoid metabolites led to apoptosis in T and B cells, indicating local glucocorticoid regeneration is functionally relevant.
Local glucocorticoid production may influence B cell selection similarly to its established role in T cell selection.
The findings suggest local glucocorticoid production could amplify changes in adrenal glucocorticoid signaling within the immune system.

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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.

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Lymphoid organs of neonatal and adult mice preferentially produce active glucocorticoids from metabolites, not precursors

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