Journal
PLOS ONE
Volume 8, Issue 1, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0054640
Keywords
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Funding
- MRC [86642]
- Wellcome Trust [083184, 064497]
- Moray Endowment fund (University of Edinburgh)
- Arthritis Research Campaign Clinician Scientist Fellowship
- MRC [G0802069, G9900991, G0800235] Funding Source: UKRI
- Medical Research Council [G0802069, G9900991, G0800235, MR/K026992/1, G0700704B] Funding Source: researchfish
- Versus Arthritis
- Cancer Research UK [20035] Funding Source: researchfish
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Mast cells are key initiators of allergic, anaphylactic and inflammatory reactions, producing mediators that affect vascular permeability, angiogenesis and fibrosis. Glucocorticoid pharmacotherapy reduces mast cell number, maturation and activation but effects at physiological levels are unknown. Within cells, glucocorticoid concentration is modulated by the 11 beta-hydroxysteroid dehydrogenases ( 11 beta-HSDs). Here we show expression and activity of 11 beta-HSD1, but not 11 beta-HSD2, in mouse mast cells with 11 beta-HSD activity only in the keto-reductase direction, regenerating active glucocorticoids (cortisol, corticosterone) from inert substrates (cortisone, 11-dehydrocorticosterone). Mast cells from 11 beta-HSD1-deficient mice show ultrastructural evidence of increased activation, including piecemeal degranulation and have a reduced threshold for IgG immune complex-induced mast cell degranulation. Consistent with reduced intracellular glucocorticoid action in mast cells, levels of carboxypeptidase A3 mRNA, a glucocorticoid-inducible mast cell-specific transcript, are lower in peritoneal cells from 11 beta-HSD1-deficient than control mice. These findings suggest that 11 beta-HSD1-generated glucocorticoids may tonically restrain mast cell degranulation, potentially influencing allergic, anaphylactic and inflammatory responses.
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