Iikura M, Suto H, Kajiwara N et al.IL-33 can promote survival, adhesion and cytokine production in human mast cells. Lab Invest 87:971-978

Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305-5324, USA.
Laboratory Investigation (Impact Factor: 3.68). 11/2007; 87(10):971-8. DOI: 10.1038/labinvest.3700663
Source: PubMed


IL-33 is a recently identified member of the IL-1 family of molecules, which also includes IL-1 and IL-18. IL-33 binds to the receptor, T1/ST2/IL-1R4, and can promote cytokine secretion by Th2 cells and NF-kappaB phosphorylation in mouse mast cells. However, the effects of these molecules, especially IL-33, in human mast cells are poorly understood. Expression of the receptors for IL-1 family molecules, specifically, IL-1R1, IL-18R and T1/ST2, was detectable intracellularly in human umbilical cord blood-derived mast cells (HUCBMCs) by flow cytometry, but was scarcely detectable on the cells' surface. However, IL-1beta, IL-18 or IL-33 induced phosphorylation of Erk, p38 and JNK in naïve HUCBMCs, and IL-33 or IL-1beta, but not IL-18, enhanced the survival of naive HUCBMCs and promoted their adhesion to fibronectin. IL-33 or IL-1beta also induced IL-8 and IL-13 production in naïve HUCBMCs, and enhanced production of these cytokines in IgE/anti-IgE-stimulated HUCBMCs, without enhancing secretion of either PGD(2) or histamine. Moreover, IL-33-mediated IL-8 production by HUCBMCs was markedly reduced by the p38 MAPK inhibitor, SB203580. In contrast to findings with mouse mast cells, IL-18 neither induced nor enhanced secretion of the mediators PGD(2) or histamine by HUCBMCs. Our findings identify previously unknown functions of IL-33 in human mast cells. One of these is that IL-33, like IL-1beta, can induce cytokine production in human mast cells even in the absence of stimuli of FcepsilonRI aggregation. Our findings thus support the hypothesis that IL-33 may enhance mast cell function in allergic disorders and other settings, either in the presence or absence of co-stimulation of mast cells via IgE/antigen-FcepsilonRI signals.

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Available from: Hajime Suto, Nov 04, 2014
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    • "Our evidence indicates that MCs can do this by producing IL-2 that in turn enhances Treg cell expansion in naive mice that lack antigen-specific IgE. IgE and specific Ag, but not IL-33, can induce degranulation of MCs (Ho et al., 2007; Iikura et al., 2007). By contrast, we found that IL- 33-stimulated MCs, but not IgE and Ag-stimulated MCs, can induce Treg cell expansion. "
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    ABSTRACT: House dust mite-derived proteases contribute to allergic disorders in part by disrupting epithelial barrier function. Interleukin-33 (IL-33), produced by lung cells after exposure to protease allergens, can induce innate-type airway eosinophilia by activating natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2), to secrete Th2 type-cytokines. Because IL-33 also can induce mast cells (MCs) to secrete Th2 type-cytokines, MCs are thought to cooperate with NH cells in enhancing protease or IL-33-mediated innate-type airway eosinophilia. However, we found that MC-deficient Kit(W-sh/W-sh) mice exhibited exacerbated protease-induced lung inflammation associated with reduced numbers of regulatory T (Treg) cells. Moreover, IL-2 produced by IL-33-stimulated MCs promoted expansion of numbers of Treg cells, thereby suppressing development of papain- or IL-33-induced airway eosinophilia. We have thus identified a unique anti-inflammatory pathway that can limit induction of innate-type allergic airway inflammation mediated by NH cells. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 07/2015; 43(1):175-86. DOI:10.1016/j.immuni.2015.06.021 · 21.56 Impact Factor
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    • "IL-33 modulates various aspects of mast cell function, including adhesion, survival, maturation and activation, through activation of the cell surface ST2 (IL-1RL1). For instance, (1) adhesion: IL-33, together with IL-1β, enhances the adhesion of human CBMC to fibronectin (Iikura et al., 2007); (2) survival: IL-33 attenuates human skin mast cell apoptosis through the anti-apoptotic molecule B-cell lymphoma-X large (BCLXL), raising the possibility of IL-33/ST2 axis as a potential target to limit mast cells in chronic inflammatory diseases (Wang et al., 2014); (3) maturation: the addition of IL-33 to in vitro cultures accelerates the maturation of CD34 + mast cell precursors into tryptase-containing cells (Allakhverdi et al., 2007); (4) activation: IL-33 exacerbates antigen-induced arthritis activating mast cells in a murine model (Xu et al., 2008); it can also synergize with IgE or IgE-independent agents, such as adenosine, C5a, SCF, NGF, PMA and TSLP, in the activation of HMC-1 (Silver et al., 2010). However, it should be noted that long exposure to IL-33 in in vitro cultures can lead to a hypo-responsive phenotype of both human and mouse mast cells (Sibilano et al., 2014). "
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    ABSTRACT: Mast cells are crucial effector cells in allergic reactions, where IgE is the best known mechanism to trigger their degranulation and release of a vast array of allergic mediators. However, IgE is not the only component to stimulate these cells to degranulate, while mast cell activation can also result in differential release of mediators. There is a plethora of stimuli, such as IgG, complement components, TLR ligands, neuropeptides, cytokines, chemokines and other inflammatory products, that can directly trigger mast cell degranulation, cause selective release of mediators, and stimulate proliferation, differentiation and/or migration. Moreover, some of these stimuli have a synergic effect on the IgE-mediated mast cell activation. Because of the ability to respond to a large repertoire of stimuli, mast cells may act as a versatile cell in various physiological and pathological conditions. In this review, we discuss current knowledge on non-IgE stimuli for (human) mast cells. Copyright © 2015. Published by Elsevier B.V.
    European journal of pharmacology 07/2015; DOI:10.1016/j.ejphar.2015.07.017 · 2.53 Impact Factor
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    • "MCs and basophils play a central role in allergic inflammation and asthma through their release of a variety of mediators. Several studies have demonstrated that binding of IL-33 and subsequent signaling leads to expression of many pro-inflammatory cytokines, chemokines and lipid mediators, including CXCL8 (IL-8), IL-5, IL-13, IL-6, IL-1 β, TNF-α, GM-CSF, CCL2 (monocyte chemoattractant protein-1) and prostaglandin D2.[61626364] The ability of IL-33 to stimulate MCs cytokine production depends in part on its ability to form a receptor complex composed of a combination of the ST2/IL-1RAcP heterodimer with c-Kit; the combination of signaling from the two receptors results in activation of multiple pathways leading to increased cytokine expression.[65] "
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    ABSTRACT: Asthma is a reversible airway obstruction that is characterized by constriction of airway smooth muscle, hyper secretion of mucus, edema and airway hyper responsiveness (AHR), mucus secretion and thickening of the basement membrane underlying the airway epithelium. During the process of airway inflammation, complex interactions of innate and adaptive immune cells as well as structural cells and their cytokines have many important roles. It was believed that airway inflammation is orchestrated by allergen specific T helper (Th) 2 cells, which recruit and accumulate in the lungs and produce a range of different effector cytokines. However, more recent studies have revealed the potential collaboration of other helper T cells and their cytokines in this process. Th17 cell may have a role in severe asthma and chronic obstructive pulmonary disease (COPD). Interleukin (IL)-9-producing subset called Th9 cell, Th22 cells which primarily secrete IL-22, IL-13 and tumor necrosis factor-α and Th25 cells via producing IL-25 are believed to be important for initiating allergic reactions and developing airway inflammation. Cytokines are important in asthma and play a critical role in orchestrating the allergic inflammatory response, although the precise role of each cytokine remains to be determined. The aim of this review is to summarize the current knowledge about the possible roles of newly identified helper T cells derived cytokines (IL-9, 17, 22, 25 and IL-33) in asthma. The potential therapeutic applications emerging from the roles of these cytokines will be discussed as well.
    05/2014; 3(1). DOI:10.4103/2277-9175.133249
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