Mast Cells Express 11 beta-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 11b-hydroxysteroid dehydrogenases (11b-HSDs). Here we show expression and activity of 11b-HSD1, but not 11b-HSD2, in mouse mast cells with 11b-HSD activity only in the keto-reductase direction, regenerating active glucocorticoids (cortisol, corticosterone) from inert substrates (cortisone, 11-dehydrocorticosterone). Mast cells from 11b-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 11b-HSD1-deficient than control mice. These findings suggest that 11b-HSD1-generated glucocorticoids may tonically restrain mast cell degranulation, potentially influencing allergic, anaphylactic and inflammatory responses. Citation: Coutinho AE, Brown JK, Yang F, Brownstein DG, Gray M, et al. (2013) Mast Cells Express 11b-hydroxysteroid Dehydrogenase Type 1: A Role in Restraining Mast Cell Degranulation. PLoS ONE 8(1): e54640. doi:10.1371/journal.pone.0054640 Editor: Kang Sun, Fudan University, China Received October 3, 2012; Accepted December 13, 2012; Published January 18, 2013 Copyright: 2013 Coutinho et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by an MRC project grant (KEC, MG, JSS, JRS, grant number 86642) and 2 Wellcome Trust Programme grants (JRS and KEC, grant number 083184 and separately, JSS, grant number 064497). Funding was also provided by the Moray Endowment fund (University of Edinburgh). MG is supported by an Arthritis Research Campaign Clinician Scientist Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: JRS holds patents on the use of 11beta-HSD1 inhibitors in diabetes, atherosclerotic disease and age-associated cognitive impairment and has been pursuing the development of 11beta-HSD1 inhibitors in an academic setting with submitted patents comprising composition of matter. There are no further patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials. * E-mail: [email protected]