Suppression of IgE-Independent Degranulation of Murine Connective Tissue-Type Mast Cells by Dexamethasone.

Keiko Yamada,Kazuma Sakamaki,Hitomi Sato,Mayumi Kamada,Nobuyuki Fukuishi,Yasushi Okuno,Satoshi Tanaka,Kazuyuki Furuta

doi:10.3390/cells8020112

Keiko Yamada, Kazuma Sakamaki + Show 6 more

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https://doi.org/10.3390/cells8020112

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Abstract

Steroidal anti-inflammatory drugs are widely used for the treatment of chronic cutaneous inflammation, such as atopic dermatitis, although it remains unknown how they modulate cutaneous mast cell functions. We investigated the effects of prolonged treatment with a synthetic glucocorticoid, dexamethasone, on murine connective tissue-type mast cells using in vitro and in vivo models. Our connective tissue-type bone marrow-derived cultured mast cell model was found to be sensitive to mast cell secretagogues, such as compound 48/80 and substance P, and higher expression levels of α subunit of a trimeric G protein, Gi1, and several Mas-related G protein-coupled receptor (Mrgpr) subtypes were observed in comparison with immature cultured mast cells. Secretagogue-induced degranulation and up-regulation of these genes was suppressed when cultured in the presence of dexamethasone. The profiles of granule constituents were drastically altered by dexamethasone. Topical application of dexamethasone down-modulated secretagogue-induced degranulation and the expression levels of several Mrgpr subtypes in cutaneous tissue. These results suggest that mast cell-mediated IgE-independent cutaneous inflammation could be suppressed by steroidal anti-inflammatory drugs through the down-regulation of G αi1 and several Mrgpr subtypes in mast cells.

Highlights

Glucocorticoid was found to have the potential to suppress inflammation in 1940s and synthetic glucocorticoids, steroidal anti-inflammatory drugs, have been widely prescribed for the treatment of various chronic inflammatory diseases, such as atopic dermatitis and autoimmune disorders [1,2].A large part of glucocorticoid-mediated effects arises through its binding to glucocorticoid receptor (GR, Nr3c1)
We first investigated the effects of dexamethasone on proliferation of bone marrow-derived cultured mast cells (BMMCs) when they were co-cultured with Swiss 3T3 fibroblasts in the presence of stem cell factor (SCF)
The number of mast cells was increased during the co-culture period, whereas it remained unchanged in the presence of dexamethasone (Figure 1a)

Summary

Introduction

Glucocorticoid was found to have the potential to suppress inflammation in 1940s and synthetic glucocorticoids, steroidal anti-inflammatory drugs, have been widely prescribed for the treatment of various chronic inflammatory diseases, such as atopic dermatitis and autoimmune disorders [1,2].A large part of glucocorticoid-mediated effects arises through its binding to glucocorticoid receptor (GR, Nr3c1). Mast cells originate in the hematopoietic stem cells in the bone marrow and undergo terminal differentiation in the tissue, in which they infiltrate via circulation [3] These findings indicated that tissue mast cells should have a greater diversity. We previously established a murine bone marrow-derived cultured mast cell model, which had similar characteristics with cutaneous mast cells, through the modification of previous models [4]. We found that this model could undergo degranulation in response to mast cell secretagogues, such as compound 48/80 and substance

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