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

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.