title: Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune system.
abstract: Systemic administration of IL-18 induces polyclonal IgE responses by causing NKT cells to express CD40 ligand and to produce IL-4. Administration of IL-33 also induces IgE response, although the mechanism underlying IgE response is unclear. Here, we compared the effects of IL-18 and IL-33 on bone marrow-derived mast cells and basophils as well as non-polarized and T(h)2-polarized CD4(+) T cells in vitro. Basophils, comprising IL-18Ralpha(+) cells (14.2%) and IL-33Ralpha(+) cells (34.6%), and mast cells, comprising IL-18Ralpha(+) cells (2.0%) and IL-33Ralpha(+) cells (95.6%), produce IL-4, IL-6, IL-13, granulocyte macrophage colony-stimulating factor (GM-CSF) and chemokines (RANTES, MIP-1alpha, MIP-1beta and MCP-1), upon stimulation with IL-18 and/or IL-33 in the presence of IL-3. Only basophils strongly produce IL-4. Furthermore, compared with mast cells, basophils produce larger amounts of the above cytokines and chemokines in response to IL-33. Level of IL-33Rbeta-mRNA expression in basophils is higher than that in mast cells. Effect of IL-33 is dependent on ST2 binding, and its signal is transduced via MyD88 in vitro. We also found that IL-2 plus IL-18 or IL-33 alone stimulates non-polarized or T(h)2-polarized CD4(+) T cells to produce IL-4 and IL-13 or IL-5 and IL-13, respectively. We finally showed that administration of IL-33 into mice ST2/MyD88 dependently induces airway hyperresponsiveness (AHR) and goblet cell hyperplasia by induction of IL-4, IL-5 and IL-13 in the lungs. Furthermore, same treatment of RAG-2(-/-) mice, lacking T and B cells, more strikingly induced AHR with marked goblet cell hyperplasia and eosinophilic infiltration in the lungs. Thus, IL-33 induces asthma-like symptom entirely independent of acquired immune system.
authors.affiliation: Department of Immunology and Medical Zoology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kondo
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Yoshimoto
authors.forename: Koubun
authors.initials: K
authors.lastname: Yasuda
authors.forename: Shizue
authors.initials: S
authors.lastname: Futatsugi-Yumikura
authors.forename: Mai
authors.initials: M
authors.lastname: Morimoto
authors.forename: Nobuki
authors.initials: N
authors.lastname: Hayashi
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Hoshino
authors.forename: Jiro
authors.initials: J
authors.lastname: Fujimoto
authors.forename: Kenji
authors.initials: K
authors.lastname: Nakanishi
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000276:immunology; D020397:Goblet Cells / Q000187:drug effects / Q000276:immunology*; D006965:Hyperplasia / Q000276:immunology; D007113:Immunity, Innate; D000072179:Interleukin-1 Receptor-Like 1 Protein; D020382:Interleukin-18 / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D000067596:Interleukin-33; D007378:Interleukins / Q000009:adverse effects* / Q000276:immunology*; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000473:pathology; D008565:Membrane Proteins / Q000172:deficiency / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000276:immunology; D018123:Receptors, Interleukin; D012130:Respiratory Hypersensitivity / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D020382:Interleukin-18; D000067596:Interleukin-33; D007378:Interleukins; D008565:Membrane Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C499308:Rag2 protein, mouse; D018123:Receptors, Interleukin