IL-33 Is Produced by Mast Cells and Regulates IgE-Dependent Inflammation

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.

Histone Deacetylase 3 Mediates Allergic Skin Inflammation by Regulating Expression of MCP1 Protein

“…Antigen stimulation induces Tip60, a histone acetyltransferase, in RBL2H3 and BMMCs. 4 It will be also necessary to examine acetylation as a cause for ubiquitination of HDAC2. The down-regulation of HDAC3 prevents Rac1 from moving to the membrane (Fig.…”

“…Passive cutaneous anaphylaxis (PCA) is IgE-and mast celldependent (4). IL-33 is produced by mast cells and mediates PCA (5).…”

The IL-33/ST2 Pathway Controls Coxsackievirus B5–Induced Experimental Pancreatitis

“…Because IL-4 is a major product of mast cells activated with IL-33 (30), and Stat6 phosphorylation is a key downstream event for IL-4-mediated signaling, we investigated the potential role of Stat6 in CVB5-induced pancreatitis. p.i., T1/ST2 2/2 mice expressed lower levels of Stat6 mRNA in the pancreas compared with WT mice.…”

Cytokine Pathways in Allergic Disease

“…Like its murine counterpart, human IL-33 can induce cytokine and chemokine production, prolong survival, and promote cell adhesion in human cord blood stem cell-derived cultured mast cells (Allakhverdi et al 2007;Iikura et al 2007). Mast cells also secrete IL-33 following activation through IgE receptors; thus, mast cell-derived IL-33 may provide a positive feedback loop that could maintain mast cell activation for an extended period of time (Hsu et al 2010). IL-33 directly activates human eosinophils, as demonstrated by superoxide anion production and degranulation, and increases eosinophil survival (Cherry et al 2008).…”