Abstract
BackgroundIL-33 is a recently characterized IL-1 family cytokine and found to be expressed in inflammatory diseases, including severe asthma and inflammatory bowl disease. Recombinant IL-33 has been shown to enhance Th2-associated immune responses and potently increase mast cell proliferation and cytokine production. While IL-33 is constitutively expressed in endothelial and epithelial cells, where it may function as a transcriptional regulator, cellular sources of IL-33 and its role in inflammation remain unclear.Methodology/Principal FindingsHere, we identify mast cells as IL-33 producing cells. IgE/antigen activation of bone marrow-derived mast cells or a murine mast cell line (MC/9) significantly enhanced IL-33. Conversely, recombinant IL-33 directly activated mast cells to produce several cytokines including IL-4, IL-5 and IL-6 but not IL-33. We show that expression of IL-33 in response to IgE-activation required calcium and that ionomycin was sufficient to induce IL-33. In vivo, peritoneal mast cells expressed IL-33 and IL-33 levels were significantly lower within the skin of mast cell deficient mice, compared to littermate controls. Local activation of mast cells promotes edema, followed by the recruitment of inflammatory cells. We demonstrate using passive cutaneous anaphylaxis, a mast cell-dependent model, that deficiency in ST2 or antibody blockage of ST2 or IL-33 ablated the late phase inflammatory response but that the immediate phase response was unaffected. IL-33 levels in the skin were significantly elevated only during the late phase.Conclusions/SignificanceOur findings demonstrate that mast cells produce IL-33 after IgE-mediated activation and that the IL-33/ST2 pathway is critical for the progression of IgE-dependent inflammation.
Highlights
Mast cells are important in both innate and adaptive responses and best characterized for their roles in defense against invading pathogens and hypersensitivity responses
Utilizing DNP-specific IgE primed Bone marrow-derived mast cells (BMMC), we show that IL-33 mRNA was upregulated within 30 minutes of stimulation and peaked at 4 hours after antigen-driven activation with DNP-HSA (Figure 1A)
To test if IL-33 was upregulated by IgE-driven activation, we investigated IL-33 levels in the skin using a passive cutaneous anaphylaxis model, whereby local mast cell activation is driven by passive IgE priming, followed by systemic antigen challenge
Summary
Mast cells are important in both innate and adaptive responses and best characterized for their roles in defense against invading pathogens and hypersensitivity responses. Activation of mast cells leads to the release of potent inflammatory mediators, including preformed mediators (e.g. histamine), lipid metabolites (e.g. prostaglandins) and a plethora of cytokines and chemokines [1]. The most characterized pathway to mast cell activation is antigen-mediated crosslinking of IgE molecules that bind via FceRI [3], that is highly expressed on mast cells and important in allergic diseases. Interleukin-33 (IL-1F11, NF-HEV) is a newly characterized cytokine belonging to the IL-1 cytokine family that includes IL-1a, IL-1b, IL-1Ra (IL-1 receptor antagonist) and IL-18 [4]. It contains an N-terminal predicted helix-turn-helix (HTH) motif responsible for nuclear translocation and chromatin binding [5] and an IL-1-like C-terminal domain. While IL-33 is constitutively expressed in endothelial and epithelial cells, where it may function as a transcriptional regulator, cellular sources of IL-33 and its role in inflammation remain unclear
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