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

Background: IL-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 Findings: Here, 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

Analysis of DNA methylation in cancer : location revisited

Changes in DNA methylation in cancer have been heralded as promising targets for the development of powerful diagnostic, prognostic, and predictive biomarkers. Despite the existence of more than 14,000 scientific publications describing DNA methylation-based biomarkers and their clinical associations in cancer, only 14 of these biomarkers have been translated into a commercially available clinical test. Methodological and experimental obstacles are both major causes of this disparity, but the genomic location of a DNA methylation-based biomarker is an intrinsic and essential property that also has an important and often overlooked role. Here, we examine the importance of the location of DNA methylation for the development of cancer biomarkers, and take a detailed look at the genomic location and other relevant characteristics of the various biomarkers with commercially available tests. We also emphasize the value of publicly available databases for the development of DNA methylation-based biomarkers and the importance of accurate reporting of the full methodological details of research findings