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* Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada;
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305;
Receptors and Signal Transduction Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892; and
Laboratory of Immune Cell Signaling, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892
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 (Ca2+) entry. However, whereas IgE+Ag more potently stimulates Ca2+ entry, it does not enhance survival under our conditions. Exploring this further, we found that whereas all five monomeric IgEs stimulate a less robust Ca2+ entry than IgE+Ag initially, they all trigger a more prolonged Ca2+ 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 Ca2+ 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 H2O2 to IgE+Ag-stimulated BMMCs leads to IL-3 secretion.
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1 This work was supported by the National Cancer Institute of Canada, with core support from the British Columbia Cancer Foundation and the British Columbia Cancer Agency. The work of J.R. and R.P.S. was supported by the intramural research programs of National Institute of Arthritis and Musculoskeletal and Skin Diseases and National Institute of Child Health and Human Development, National Institutes of Health.
2 Address correspondence and reprint requests to Dr. Gerald Krystal, British Columbia Cancer Research Centre, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3. E-mail address: gkrystal{at}bccrc.ca
3 Abbreviations used in this paper: mIgE, monomeric IgE; 
, clone 91.58 anti-nitrophenol; 5-LO, 5-lipoxygenase; 48, anti-DNP clone DNP48; BMMC, bone marrow-derived mast cell; CM-DCFHDA, 5-(and 6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate; DMF, dimethylformamide; E, anti-Epo26; HSA, human serum albumin; L, H1 26.82 Liu anti-DNP; LAT, linker for activation of T cells; MKP, MAPK phosphatase; MTG, monothioglycerol; NAC, N-acetylcysteine; P/S, penicillin/streptomycin; PLC, phospholipase C; ROS, reactive oxygen species; S, clone SPE-7 anti-DNP; SCF, stem cell factor.
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