IgE-Induced Mast Cell Survival Requires the Prolonged Generation of Reactive Oxygen Species

• Published in: The Journal of immunology (1950) 2008-09, Vol.181 (6), p.3850-3860
• Main Authors: Sly, Laura M, Kalesnikoff, Janet, Lam, Vivian, Wong, Dana, Song, Christine, Omeis, Stephanie, Chan, Karen, Lee, Corinna W. K, Siraganian, Reuben P, Rivera, Juan, Krystal, Gerald
• Format: Article
• Language: English
• Subjects: Animals; Calcium - metabolism; Cell Survival - immunology; Cells, Cultured; Extracellular Space - enzymology; Extracellular Space - metabolism; Humans; Immunoglobulin E - physiology; Interleukin-3 - biosynthesis; Interleukin-3 - physiology; Mast Cells - cytology; Mast Cells - enzymology; Mast Cells - immunology; Mast Cells - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Phosphorylation; Time Factors
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.181.6.3850

We show in this study that the ability of five different monomeric IgEs to enhance murine bone marrow-derived mast cell (BMMC) survival correlates with their ability to stimulate extracellular calcium (Ca(2+)) entry. However, whereas IgE+Ag more potently stimulates Ca(2+) entry, it does not enhance survival under our conditions. Exploring this further, we found that whereas all five monomeric IgEs stimulate a less robust Ca(2+) entry than IgE+Ag initially, they all trigger a more prolonged Ca(2+) influx, generation of reactive oxygen species (ROS), and ERK phosphorylation. These prolonged signaling events correlate with their survival-enhancing ability and positively feedback on each other to generate the prosurvival cytokine, IL-3. Interestingly, the prolonged ERK phosphorylation induced by IgE appears to be regulated by a MAPK phosphatase rather than MEK. IgE-induced ROS generation, unlike that triggered by IgE+Ag, is not mediated by 5-lipoxygenase. Moreover, ROS inhibitors, which block both IgE-induced ROS production and Ca(2+) influx, convert the prolonged ERK phosphorylation induced by IgE into the abbreviated phosphorylation pattern observed with IgE+Ag and prevent IL-3 generation. In support of the essential role that IgE-induced ROS plays in IgE-enhanced BMMC survival, we found the addition of H(2)O(2) to IgE+Ag-stimulated BMMCs leads to IL-3 secretion.