IL-33 Mediates Inflammatory Responses in Human Lung Tissue Cells

Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
The Journal of Immunology (Impact Factor: 4.92). 10/2010; 185(10):5743-50. DOI: 10.4049/jimmunol.0903818
Source: PubMed


IL-33 is a member of the IL-1 family and mediates its biological effects via the ST2 receptor, which is selectively expressed on Th2 cells and mast cells. Although polymorphic variation in ST2 is strongly associated with asthma, it is currently unclear whether IL-33 acts directly on lung tissue cells at sites of airway remodeling. Therefore, we aimed to identify the IL-33-responsive cells among primary human lung tissue cells. ST2 mRNA was expressed in both endothelial and epithelial cells but not in fibroblasts or smooth muscle cells. Correspondingly, IL-33 promoted IL-8 production by both endothelial and epithelial cells but not by fibroblasts or smooth muscle cells. Transfection of ST2 small interference RNA into both endothelial and epithelial cells significantly reduced the IL-33-dependent upregulation of IL-8, suggesting that IL-33-mediated responses in these cells occur via the ST2 receptor. Importantly, Th2 cytokines, such as IL-4, further enhanced ST2 expression and function in both endothelial and epithelial cells. The IL-33-mediated production of IL-8 by epithelial cells was almost completely suppressed by corticosteroid treatment. In contrast, the effect of corticosteroid treatment on the IL-33-mediated responses of endothelial cells was only partial. IL-33 induced activation of both ERK and p38 MAPK in endothelial cells but only ERK in epithelial cells. p38 MAPK was required for the IL-33-mediated responses of endothelial cells, whereas ERK was required for IL-33-mediated IL-8 production by epithelial cells. Taken together, these findings suggest that IL-33-mediated inflammatory responses of lung tissue cells may be involved in the chronic allergic inflammation of the asthmatic airway.

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Available from: Hideaki Morita, Oct 27, 2015
    • "Interleukin-33 (IL-33), a member of the IL1 cytokine family, is mainly associated with the induction of T-helper type 2 (Th2) immune response through its receptor, ST2 [1]. Several immune cell types express IL-33, such as macrophages and dendritic cells, as do non-immune cells, such as endothelial cells, epithelial cells and fibroblasts [1] [2] [3] [4]. IL33 was initially described as a nuclear repressor factor, and later identified as an extracellular ligand for ST2 [1] [2]. "
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    ABSTRACT: IL-33, an IL-1 family member, is expressed by many cell types and can regulate gene transcription. IL-33 is released upon cell necrosis and the precursor form is enzymatically processed, and then drives inflammation as a damage-associated molecular pattern. The IL-33 receptor ST2, encoded by IL1RL1, is expressed as both a membrane-anchored receptor (ST2L) activated by IL-33, and as a soluble variant (sST2) that exhibits anti-inflammatory properties. The IL-33/ST2 axis is involved in the pathogenesis of atopic and autoimmune diseases, cancer, and central nervous system disorders. Here, we review recent findings on the role of the IL-33/ST2 axis in health and disease. Copyright © 2015 Elsevier Ltd. All rights reserved.
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    • "IL-33R (or ST2) is selectively expressed on Th2 cells (where it stimulates the production of IL-4) and on mast cells.167,170 Soluble ST2 receptor is considered anti-inflammatory in animal models,171 and its plasma level is increased in mild/moderate stable COPD compared to control smokers with normal lung function.172 "
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    • "Normal human bronchial epithelial cells (NHBEs), normal human coronary artery endothelial cells (HCAECs) and normal human lung fibroblasts (NHLF) were obtained from Lonza (Wakersville, MD, USA) and were cultured as described elsewhere. [31]. "
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