International Immunology Advance Access originally published online on April 29, 2008
International Immunology 2008 20(6):791-800; doi:10.1093/intimm/dxn037
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Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune system
1 Department of Immunology and Medical Zoology
2 Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
3 Collaborative Development of Innovation Seeds, Japan Science and Technology Corporation, Saitama 332-0012, Japan
4 Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
5 Division of Respirology, Neurology and Rheumatology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
Correspondence to: K. Nakanishi; E-mail: nakaken{at}hyo-med.ac.jp
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 Th2-polarized CD4+ T cells in vitro. Basophils, comprising IL-18R
+ cells (14.2%) and IL-33R+ cells (34.6%), and mast cells, comprising IL-18R+ cells (2.0%) and IL-33R+ cells (95.6%), produce IL-4, IL-6, IL-13, granulocyte macrophage colony-stimulating factor (GM-CSF) and chemokines (RANTES, MIP-1, MIP-1β 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-33Rβ-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 Th2-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.
Keywords: basophils, IL-33, innate immunity, ST2, Th2 cytokines
* These authors contributed equally to this study.
Transmitting editor: T. Hamaoka
Received 6 February 2008, accepted 26 March 2008.
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