title: Dexamethasone rapidly suppresses IL-33-stimulated mast cell function by blocking transcription factor activity.
abstract: Mast cells are critical effectors of allergic disease and can be activated by IL-33, a proinflammatory member of the IL-1 cytokine family. IL-33 worsens the pathology of mast cell-mediated diseases, but therapies to antagonize IL-33 are still forthcoming. Because steroids are the mainstay of allergic disease treatment and are well known to suppress mast cell activation by other stimuli, we examined the effects of the steroid dexamethasone on IL-33-mediated mast cell function. We found that dexamethasone potently and rapidly suppressed cytokine production elicited by IL-33 from murine bone marrow-derived and peritoneal mast cells. IL-33 enhances IgE-mediated mast cell cytokine production, an activity that was also antagonized by dexamethasone. These effects were consistent in human mast cells. We additionally observed that IL-33 augmented migration of IgE-sensitized mast cells toward antigen. This enhancing effect was similarly reversed by dexamethasone. Simultaneous addition of dexamethasone with IL-33 had no effect on the phosphorylation of MAP kinases or NFκB p65 subunit; however, dexamethasone antagonized AP-1- and NFκB-mediated transcriptional activity. Intraperitoneal administration of dexamethasone completely abrogated IL-33-mediated peritoneal neutrophil recruitment and prevented plasma IL-6 elevation. These data demonstrate that steroid therapy may be an effective means of antagonizing the effects of IL-33 on mast cells in vitro and in vivo, acting partly by suppressing IL-33-induced NFκB and AP-1 activity.
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, Virginia, USA; and.
authors.forename: Anuya
authors.initials: A
authors.lastname: Paranjape
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, Virginia, USA; and.
authors.forename: Oksana
authors.initials: O
authors.lastname: Chernushevich
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, Virginia, USA; and.
authors.forename: Amina Abdul
authors.initials: AA
authors.lastname: Qayum
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, Virginia, USA; and.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Spence
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, Virginia, USA; and.
authors.forename: Marcela T
authors.initials: MT
authors.lastname: Taruselli
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, Virginia, USA; and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Abebayehu
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, Virginia, USA; and.
authors.forename: Brian O
authors.initials: BO
authors.lastname: Barnstein
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, Virginia, USA; and.
authors.forename: Jamie Josephine Avila
authors.initials: JJ
authors.lastname: McLeod
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, Virginia, USA; and.
authors.forename: Bianca
authors.initials: B
authors.lastname: Baker
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, Virginia, USA; and.
authors.forename: Gurjas S
authors.initials: GS
authors.lastname: Bajaj
authors.affiliation: Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, USA.
authors.forename: Alena P
authors.initials: AP
authors.lastname: Chumanevich
authors.affiliation: Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, USA.
authors.forename: Carole A
authors.initials: CA
authors.lastname: Oskeritzian
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, Virginia, USA; and jjryan@vcu.edu.
authors.forename: John J
authors.initials: JJ
authors.lastname: Ryan
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology*; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000096:biosynthesis / Q000235:genetics; D000067596:Interleukin-33 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008407:Mast Cells / Q000187:drug effects*; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D015735:Mifepristone / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D012867:Skin / Q000473:pathology; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D016207:Cytokines; C506536:IL33 protein, human; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D011965:Receptors, Glucocorticoid; D011994:Recombinant Proteins; D014157:Transcription Factors; D015735:Mifepristone; D007073:Immunoglobulin E; D003907:Dexamethasone
keywords: AP-1; NFκB; ST2; glucocorticoid; inflammation; neutrophil recruitment