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

Abstract

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.

Human Vitamin K 2,3-Epoxide Reductase Complex Subunit 1-like 1 (VKORC1L1) Mediates Vitamin K-dependent Intracellular Antioxidant Function

“…S3a, blue bars). Surprisingly, these results correlate well with recent reports of intense and protracted ROS bursts, which are characteristic of these cell types during normal physiological function (37)(38)(39)(40). Thus, independent results from these studies further point to specific roles for VKORC1L1 in intracellular redox homeostasis as well as in response to acute ROS-induced oxidative stress.…”

“…Mast cells have recently been shown to generate prolonged, high concentrations of ROS upon activation by binding IgE on the cell surface (39,40). Several years earlier, the results of a genome-wide high density oligonucleotide array study of mouse mRNA expression included data for both VKORC1L1 and VKORC1 in mast cells at rest or activated by IgE (supplemental Fig.…”

Anti-Inflammatory Effects of Electroacupuncture in the Respiratory System of a Symptomatic Amyotrophic Lateral Sclerosis Animal Model

“…ERKs are widely expressed protein kinase intracellular signaling molecules that are associated with a variety of biological responses; these responses include cell proliferation, migration, differentiation, and apoptosis depending upon cell type, stimulus, and the duration or degree of activation [36][37][38][39] . The ERK pathway has been considered to be a pro-survival pathway in mast cells [40] and thymocytes [41] . In this pathway, active ERKs and AKT are translocated to the nucleus where they can phosphorylate certain transcription factors and regulate the expression of specific genes that contribute to cell survival [42] .…”

Antibodies and IL-3 support helminth-induced basophil expansion

“…IgE stimulation of murine mast cells (24) or human basophils (25) can result in IL-3 production and proliferation in vitro, raising the possibility that antibodies act to elicit autocrine IL-3 production by basophils in vivo following helminth infection. We first determined that either IgE or IgG1 cross-linking could promote IL-3 mRNA expression by bone-marrow-derived murine basophils in vitro (Fig.…”