title: Glucocorticoids inhibit the cytokine-induced proliferation of mast cells, the high affinity IgE receptor-mediated expression of TNF-alpha, and the IL-10-induced expression of chymases.
abstract: Mast cells are a heterogeneous family of immune cells that, when activated through their high affinity IgE receptors (Fc epsilonRI), release various granule mediators (e.g., neutral proteases and serglycin proteoglycans) and proinflammatory cytokines (e.g., IL-6 and TNF-alpha). We and others have shown that the growth and differentiation of immature, nontransformed mouse bone marrow-derived mast cells (mBMMC) can be regulated in vitro by IL-3, IL-10, and c-kit ligand. We now report that glucocorticoids inhibit the c-kit ligand- and IL-3-induced proliferation of mBMMC, the Fc epsilonRI-mediated expression of TNF-alpha, and the IL-10-mediated expression of the two chymases designated mouse mast cell protease (mMCP)-1 and mMCP-2. In contrast, glucocorticoids induce mBMMC to increase their expression of serglycin proteoglycan and carboxypeptidase A. As assessed by nuclear run-on and RNA blot analyses, dexamethasone inhibited the IL-10-mediated expression of mMCP-1 and mMCP-2, primarily by inducing rapid degradation of their transcripts. The stimulative effect on serglycin proteoglycan expression and the inhibitory effect on chymase expression were dose and time dependent and glucocorticoid specific. These findings indicate that glucocorticoids exert profound and diverse effects on the growth, cytokine expression, and granule differentiation of mouse mast cells, and that at least some of this regulation occurs through a post-transcriptional mechanism.
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: K K
authors.initials: KK
authors.lastname: Eklund
authors.forename: D E
authors.initials: DE
authors.lastname: Humphries
authors.forename: Z
authors.initials: Z
authors.lastname: Xia
authors.forename: N
authors.initials: N
authors.lastname: Ghildyal
authors.forename: D S
authors.initials: DS
authors.lastname: Friend
authors.forename: V
authors.initials: V
authors.lastname: Gross
authors.forename: R L
authors.initials: RL
authors.lastname: Stevens
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells; D015550:Cell Degranulation / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D053818:Chymases; D016207:Cytokines / Q000502:physiology*; D003594:Cytoplasmic Granules / Q000201:enzymology; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D016753:Interleukin-10 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D017455:Receptors, IgE / Q000502:physiology*; D012697:Serine Endopeptidases / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D005938:Glucocorticoids; D015850:Interleukin-6; D017455:Receptors, IgE; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D003907:Dexamethasone; D012697:Serine Endopeptidases; C083294:chymase 2; D053818:Chymases; C509229:Cma2 protein, mouse