Silver MR, Margulis A, Wood N et al.IL-33 synergizes with IgE-dependent and IgE-independent agents to promote mast cell and basophil activation. Inflamm Res 59:207-218

Inflammation Research, Wyeth, 200 Cambridge Park Drive, Cambridge, MA, 02140, USA.
Agents and Actions (Impact Factor: 2.35). 09/2009; 59(3):207-18. DOI: 10.1007/s00011-009-0088-5
Source: PubMed


Mast cell and basophil activation contributes to inflammation, bronchoconstriction, and airway hyperresponsiveness in asthma. Because IL-33 expression is inflammation inducible, we investigated IL-33-mediated effects in concert with both IgE-mediated and IgE-independent stimulation.
Because the HMC-1 mast cell line can be activated by GPCR and RTK signaling, we studied the effects of IL-33 on these pathways. The IL-33- and SCF-stimulated HMC-1 cells were co-cultured with human lung fibroblasts and airway smooth muscle cells in a collagen gel contraction assay. IL-33 effects on IgE-mediated activation were studied in primary mast cells and basophils.
IL-33 synergized with adenosine, C5a, SCF, and NGF receptor activation. IL-33-stimulated and SCF-stimulated HMC-1 cells demonstrated enhanced collagen gel contraction when cultured with fibroblasts or smooth muscle cells. IL-33 also synergized with IgE receptor activation of primary human mast cells and basophils.
IL-33 amplifies inflammation in both IgE-independent and IgE-dependent responses.

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    • "There are various mechanisms for the action of IL-33 on mast cells. First, IL-33 may activate mast cells to release various cytokines, chemokines, and lipid mediators without degranulation (Allakhverdi et al., 2007; Ho et al., 2007; Moulin et al., 2007; Silver et al., 2010). Second, IL-33 may enhance the release of these cytokines, chemokines, and lipid mediators from mast cells in a degranulation-dependent or -independent fashion after stimulation with FcεRI or other receptors such as the substance P receptor (Theoharides et al., 2010). "
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    ABSTRACT: Inflammation is defined as a physiological response initiated by a variety of conditions that cause insult to the body, such as infection and tissue injury. Inflammation is triggered by specialized receptors in the innate immune system, which recognize microbial components known as pathogen-associated molecular patterns or endogenous signals produced by damaged cells (damage-associated molecular patterns). IL-33 is a cytokine that is released predominantly at the epithelial barrier when it is exposed to pathogens, allergens, or injury-inducing stimuli. IL-33 target cells are various, ranging from hematopoietic stem and progenitor cells (HSPCs) and essentially all types of their progeny to many non-hematopoietic cells. The pleiotropic actions of IL-33 suggest that IL-33 is involved in every phase of the inflammatory process. In this review, we discuss recent advances in the understanding of how IL-33 orchestrates inflammatory responses by regulating HSPCs and innate immune cells.
    Full-text · Article · May 2013 · Frontiers in Immunology
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    • "As there is a documented association between IL-33 expression and mast cell activation in several inflammatory conditions,[20], [21], [23]–[26] we evaluated mast cell activation in our experimental models. We detected mast cell degranulation in the pancreas and lung in mice and rats with ligation-induced acute pancreatitis, which when taken together with increased IL-33 expression suggests that interactions between IL-33 and mast cells may play a role in disease pathogenesis. "
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    ABSTRACT: Acute pancreatitis is potentially fatal but treatment options are limited as disease pathogenesis is poorly understood. IL-33, a novel IL-1 cytokine family member, plays a role in various inflammatory conditions but its role in acute pancreatitis is not well understood. Specifically, whether pancreatic acinar cells produce IL-33 when stressed or respond to IL-33 stimulation, and whether IL-33 exacerbates acute pancreatic inflammation is unknown. In duct ligation-induced acute pancreatitis in mice and rats, we found that (a) IL-33 concentration was increased in the pancreas; (b) mast cells, which secrete and also respond to IL-33, showed degranulation in the pancreas and lung; (c) plasma histamine and pancreatic substance P concentrations were increased; and (d) pancreatic and pulmonary proinflammatory cytokine concentrations were increased. In isolated mouse pancreatic acinar cells, TNF-α stimulation increased IL-33 release while IL-33 stimulation increased proinflammatory cytokine release, both involving the ERK MAP kinase pathway; the flavonoid luteolin inhibited IL-33-stimulated IL-6 and CCL2/MCP-1 release. In mice without duct ligation, exogenous IL-33 administration induced pancreatic inflammation without mast cell degranulation or jejunal inflammation; pancreatic changes included multifocal edema and perivascular infiltration by neutrophils and some macrophages. ERK MAP kinase (but not p38 or JNK) and NF-kB subunit p65 were activated in the pancreas of mice receiving exogenous IL-33, and acinar cells isolated from the pancreas of these mice showed increased spontaneous cytokine release (IL-6, CXCL2/MIP-2α). Also, IL-33 activated ERK in human pancreatic tissue. As exogenous IL-33 does not induce jejunal inflammation in the same mice in which it induces pancreatic inflammation, we have discovered a potential role for an IL-33/acinar cell axis in the recruitment of neutrophils and macrophages and the exacerbation of acute pancreatic inflammation. IL-33 is induced in acute pancreatitis, activates acinar cell proinflammatory pathways and exacerbates acute pancreatic inflammation.
    Full-text · Article · Mar 2013 · PLoS ONE
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    • "Acting via its receptor ST2, IL-33 triggers MCs to release numerous cytokines and chemokines [16], [17], [18], [19], [20], [21], [22], an activity implicated in the pathogenesis of anaphylaxis and in the role of mast cells as sensors of tissue injury [22], [23]. Moreover, exposure of MCs to IL-33 augments expression of cytokines in MCs activated concomitantly via the high-affinity IgE receptor FcεRI [24], [25]. IL-33 is also the first factor shown to promote the accumulation in granules of mouse MC protease 6 [26], an ortholog of human tryptase β that plays a role in innate immunity and inflammatory arthritis [27], [28], [29]. "
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    ABSTRACT: Mast cells (MCs) are heterogeneous cells whose phenotype is modulated by signals received from the local microenvironment. Recent studies have identified the mesenchymal-derived cytokine IL-33 as a potent direct activator of MCs, as well as regulator of their effector phenotype, and have implicated this activity in the ability of mast cells to contribute to murine experimental arthritis. We explored the hypothesis that IL-33 enables participation of synovial MCs in murine K/BxN arthritis by promoting their activation by IgG immune complexes. Compared to wild-type (WT) control mice, transgenic animals lacking the IL-33 receptor ST2 exhibited impaired MC-dependent immune complex-induced vascular permeability (flare) and attenuated K/BxN arthritis. Whereas participation of MCs in this model is mediated by the activating IgG receptor FcγRIII, we pre-incubated bone marrow-derived MCs with IL-33 and found not only direct induction of cytokine release but also a marked increase in FcγRIII-driven production of critical arthritogenic mediators including IL-1β and CXCL2. This "priming" effect was associated with mRNA accumulation rather than altered expression of Fcγ receptors, could be mimicked by co-culture of WT but not ST2(-/-) MCs with synovial fibroblasts, and was blocked by antibodies against IL-33. In turn, WT but not ST2(-/-) MCs augmented fibroblast expression of IL-33, forming a positive feedback circuit. Together, these findings confirm a novel role for IL-33 as an amplifier of IgG immune complex-mediated inflammation and identify a potential MC-fibroblast amplification loop dependent on IL-33 and ST2.
    Full-text · Article · Oct 2012 · PLoS ONE
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