title: IL-33 induces a hyporesponsive phenotype in human and mouse mast cells.
abstract: IL-33 is elevated in afflicted tissues of patients with mast cell (MC)-dependent chronic allergic diseases. Based on its acute effects on mouse MCs, IL-33 is thought to play a role in the pathogenesis of allergic disease through MC activation. However, the manifestations of prolonged IL-33 exposure on human MC function, which best reflect the conditions associated with chronic allergic disease, are unknown. In this study, we found that long-term exposure of human and mouse MCs to IL-33 results in a substantial reduction of MC activation in response to Ag. This reduction required >72 h exposure to IL-33 for onset and 1-2 wk for reversion following IL-33 removal. This hyporesponsive phenotype was determined to be a consequence of MyD88-dependent attenuation of signaling processes necessary for MC activation, including Ag-mediated calcium mobilization and cytoskeletal reorganization, potentially as a consequence of downregulation of the expression of phospholipase Cγ(1) and Hck. These findings suggest that IL-33 may play a protective, rather than a causative, role in MC activation under chronic conditions and, furthermore, reveal regulated plasticity in the MC activation phenotype. The ability to downregulate MC activation in this manner may provide alternative approaches for treatment of MC-driven disease.
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Mi-Yeon
authors.initials: MY
authors.lastname: Jung
authors.forename: Daniel
authors.initials: D
authors.lastname: Smrž
authors.forename: Avanti
authors.initials: A
authors.lastname: Desai
authors.forename: Geethani
authors.initials: G
authors.lastname: Bandara
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Ito
authors.forename: Shoko
authors.initials: S
authors.lastname: Iwaki
authors.forename: Jeong-Han
authors.initials: JH
authors.lastname: Kang
authors.forename: Marcus V
authors.initials: MV
authors.lastname: Andrade
authors.forename: Susana C
authors.initials: SC
authors.lastname: Hilderbrand
authors.forename: Jared M
authors.initials: JM
authors.lastname: Brown
authors.forename: Michael A
authors.initials: MA
authors.lastname: Beaven
authors.forename: Dean D
authors.initials: DD
authors.lastname: Metcalfe
authors.forename: Alasdair M
authors.initials: AM
authors.lastname: Gilfillan
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007165:Immunosuppression Therapy; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000276:immunology* / Q000494:pharmacology; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D010641:Phenotype; D051966:Phospholipase C gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects; D051572:Proto-Oncogene Proteins c-hck / Q000235:genetics / Q000276:immunology; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology
chemical_list: D000199:Actins; C506536:IL33 protein, human; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D053594:Myeloid Differentiation Factor 88; D018123:Receptors, Interleukin; D051572:Proto-Oncogene Proteins c-hck; D051966:Phospholipase C gamma