Mast cells express 11β-hydroxysteroid dehydrogenase type 1: a role in restraining mast cell degranulation.
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 11β-hydroxysteroid dehydrogenases (11β-HSDs). Here we show expression and activity of 11β-HSD1, but not 11β-HSD2, in mouse mast cells with 11β-HSD activity only in the keto-reductase direction, regenerating active glucocorticoids (cortisol, corticosterone) from inert substrates (cortisone, 11-dehydrocorticosterone). Mast cells from 11β-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 11β-HSD1-deficient than control mice. These findings suggest that 11β-HSD1-generated glucocorticoids may tonically restrain mast cell degranulation, potentially influencing allergic, anaphylactic and inflammatory responses.
University/British Heart Foundation Centre for Cardiovascular Research, University of Edinburgh, Edinburgh, United Kingdom.
Agnes E
AE
Coutinho
Jeremy K
JK
Brown
Fu
F
Yang
David G
DG
Brownstein
Mohini
M
Gray
Jonathan R
JR
Seckl
John S
JS
Savill
Karen E
KE
Chapman
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics / Q000378:metabolism; D000707:Anaphylaxis / Q000201:enzymology; D000818:Animals; D043422:Carboxypeptidases A / Q000378:metabolism; D015550:Cell Degranulation; D003345:Corticosterone / Q000096:biosynthesis* / Q000378:metabolism; D015870:Gene Expression; D006854:Hydrocortisone / Q000096:biosynthesis* / Q000378:metabolism; D006967:Hypersensitivity / Q000201:enzymology; D007249:Inflammation / Q000201:enzymology; D008407:Mast Cells / Q000201:enzymology*; D051379:Mice
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D043422:Carboxypeptidases A; C503326:Cpa3 protein, mouse; D003345:Corticosterone; D006854:Hydrocortisone