Suppression of IgE-independent degranulation of murine mast cells by dexamethasone

Abstract

Background: Steroidal anti-inflammatory drugs have been often used for therapy of chronic inflammatory diseases, such as atopic dermatitis, although the mechanism of their actions remains to be clarified in detail. We investigated the effects of one of steroidal anti-inflammatory drugs, dexamethasone, on the process of murine mast cell maturation and degranulation in response to various mast cell secretagogues. Methods: A mature mast cell model was established by performing co-culture of IL-3-dependent murine bone marrowderived cultured mast cells with Swiss 3T3 fibroblasts in the presence of c-kit ligand. Various indices related to mast cell maturation, such as granule protease expression, histamine content, and degranulation in response to various secretagogues, were compared between in the absence and presence of dexamethasone. Dexamethasone was applied on the surface of ear pinna of BALB/c mice for 6 days and degranulation of cutaneous mast cells stimulated with secretagogues was investigated. Results: Prolonged treatment with dexamethasone (1 μM) during the co-culture period suppressed the proliferation, upregulation of chymase, and degranulation induced by compound 48/80 or substance P, but augmented the granule storage of histamine, carboxypeptidase A and β-hexosaminidase. Expression levels of α subunit of the trimeric G protein, Gα i1 and several members of Mas-related G protein-coupled receptors (Mrgpr) were up-regulated during the co-culture period and returned to the basal levels in the presence of dexamethasone. Although 6 days of cutaneous application of dexamethasone did not change the number of mast cells, it augmented cutaneous histamine content and significantly suppressed degranulation in response to compound 48/80 and IgE-mediated antigen stimulation. Conclusion: Dexamethasone affected the granule contents and lowered the sensitivity to secretagogues of murine mature cultured mast cells. Down-regulation of Mrgpr family genes and Gα i1 in mast cells by dexamethasone might be involved in the therapeutic effects on chronic dermatitis.