Mast Cells Express 11 beta-hydroxysteroid Dehydrogenase Type 1: A Role in Restraining Mast Cell Degranulation: a role in restraining mast cell degranulation

Agnes E. Coutinho; Jeremy K. Brown; Fu Yang; David G. Brownstein; Mohini Gray; Jonathan R. Seckl; John S. Savill; Karen E. Chapman

doi:10.1371/journal.pone.0054640

Mast Cells Express 11 beta-hydroxysteroid Dehydrogenase Type 1: A Role in Restraining Mast Cell Degranulation: a role in restraining mast cell degranulation

Agnes E. Coutinho, Jeremy K. Brown, Fu Yang, David G. Brownstein, Mohini Gray, Jonathan R. Seckl, John S. Savill, Karen E. Chapman^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Article number	ARTN e54640
Number of pages	8
Journal	PLoS ONE
Volume	8
Issue number	1
DOIs	https://doi.org/10.1371/journal.pone.0054640
Publication status	Published - 18 Jan 2013

Keywords / Materials (for Non-textual outputs)

ARTHRITIS
ACTIVATION
PROMOTES
11-BETA-HSD1
GLUCOCORTICOIDS
MICE
HOMOLOGS
PITUITARY-ADRENAL AXIS
IN-VIVO
INFLAMMATION

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10.1371/journal.pone.0054640

Mast Cells Express 11 beta-hydroxysteroid Dehydrogenase Type 1: A Role in Restraining Mast Cell Degranulation
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http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054640

Endogenous suppression of lung inflammation
Savill, J. (Principal Investigator)
MRC
1/04/09 → 31/03/16
Project: Research
How does 11B-hydroxysteriod dehydrogenase type 1 limit inflammation.
Chapman, K. (Principal Investigator), Gray, M. (Co-investigator), Savill, J. (Co-investigator) & Seckl, J. (Co-investigator)
MRC
1/10/08 → 30/04/12
Project: Research
11Beta hydroxystereoid dehydrogenase type 1 and atheroscerosis risk.
Chapman, K. (Principal Investigator), Mullins, J. (Co-investigator), Savill, J. (Co-investigator), Seckl, J. (Co-investigator) & Walker, B. (Co-investigator)
UK-based charities
1/01/08 → 31/05/13
Project: Research

Cite this

@article{51a270d5b4064f309a4e8016b4635954,

title = "Mast Cells Express 11 beta-hydroxysteroid Dehydrogenase Type 1: A Role in Restraining Mast Cell Degranulation: a role in restraining mast cell degranulation",

abstract = "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.",

keywords = "ARTHRITIS, ACTIVATION, PROMOTES, 11-BETA-HSD1, GLUCOCORTICOIDS, MICE, HOMOLOGS, PITUITARY-ADRENAL AXIS, IN-VIVO, INFLAMMATION",

author = "Coutinho, {Agnes E.} and Brown, {Jeremy K.} and Fu Yang and Brownstein, {David G.} and Mohini Gray and Seckl, {Jonathan R.} and Savill, {John S.} and Chapman, {Karen E.}",

note = "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.",

year = "2013",

month = jan,

day = "18",

doi = "10.1371/journal.pone.0054640",

language = "English",

volume = "8",

journal = "PLoS ONE",

issn = "1932-6203",

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T1 - Mast Cells Express 11 beta-hydroxysteroid Dehydrogenase Type 1: A Role in Restraining Mast Cell Degranulation

T2 - a role in restraining mast cell degranulation

AU - Coutinho, Agnes E.

AU - Brown, Jeremy K.

AU - Yang, Fu

AU - Brownstein, David G.

AU - Gray, Mohini

AU - Seckl, Jonathan R.

AU - Savill, John S.

AU - Chapman, Karen E.

N1 - 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.

PY - 2013/1/18

Y1 - 2013/1/18

N2 - 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.

AB - 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.

KW - ARTHRITIS

KW - ACTIVATION

KW - PROMOTES

KW - 11-BETA-HSD1

KW - GLUCOCORTICOIDS

KW - MICE

KW - HOMOLOGS

KW - PITUITARY-ADRENAL AXIS

KW - IN-VIVO

KW - INFLAMMATION

U2 - 10.1371/journal.pone.0054640

DO - 10.1371/journal.pone.0054640

M3 - Article

C2 - 23349944

SN - 1932-6203

VL - 8

JO - PLoS ONE

JF - PLoS ONE

IS - 1

M1 - ARTN e54640

ER -

Mast Cells Express 11 beta-hydroxysteroid Dehydrogenase Type 1: A Role in Restraining Mast Cell Degranulation: a role in restraining mast cell degranulation

Abstract

Keywords / Materials (for Non-textual outputs)

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Projects

Endogenous suppression of lung inflammation

How does 11B-hydroxysteriod dehydrogenase type 1 limit inflammation.

11Beta hydroxystereoid dehydrogenase type 1 and atheroscerosis risk.

Cite this