Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune system

Int Immunol. 2008 Jun;20(6):791-800. doi: 10.1093/intimm/dxn037. Epub 2008 Apr 29.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokines / immunology
  • Cytokines / metabolism
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / immunology
  • Goblet Cells / drug effects
  • Goblet Cells / immunology*
  • Hyperplasia / immunology
  • Immunity, Innate*
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-18 / administration & dosage
  • Interleukin-18 / immunology
  • Interleukin-18 / metabolism
  • Interleukin-33
  • Interleukins / adverse effects*
  • Interleukins / immunology*
  • Leukocytes / drug effects
  • Leukocytes / immunology
  • Leukocytes / metabolism
  • Lung / immunology
  • Lung / pathology
  • Membrane Proteins / deficiency
  • Membrane Proteins / immunology
  • Mice
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / deficiency
  • Myeloid Differentiation Factor 88 / immunology
  • Receptors, Interleukin
  • Respiratory Hypersensitivity / immunology*
  • Signal Transduction / immunology
  • Th2 Cells / drug effects
  • Th2 Cells / immunology
  • Th2 Cells / metabolism


  • Cytokines
  • DNA-Binding Proteins
  • Il1rl1 protein, mouse
  • Il33 protein, mouse
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-18
  • Interleukin-33
  • Interleukins
  • Membrane Proteins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Rag2 protein, mouse
  • Receptors, Interleukin