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The Journal of Immunology, 2003, 171: 6119-6127.
Copyright © 2003 by The American Association of Immunologists

Fc{epsilon}RI Signaling of Mast Cells Activates Intracellular Production of Hydrogen Peroxide: Role in the Regulation of Calcium Signals 1

Yoshihiro Suzuki2, Tetsuro Yoshimaru, Takashi Matsui, Toshio Inoue, Osamu Niide, Satoshi Nunomura and Chisei Ra

Division of Molecular Cell Immunology and Allergology, Nihon University Graduate School of Medical Sciences, Tokyo, Japan

Earlier studies, including our own, revealed that activation of mast cells is accompanied by production of reactive oxygen species (ROS) that help to mediate the release of the inflammatory mediators, including histamine and eicosanoids. However, little is known about the mechanisms of ROS production, including the species of oxidants produced. In this study we show that in both the RBL-2H3 mast cell line and bone marrow-derived mast cells, Fc{epsilon}RI cross-linking stimulates intracellular oxidative burst, including hydrogen peroxide (H2O2) production, as defined with the oxidant-sensitive dyes dichlorofluorescein and scopoletin and the selective scavenger ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one). The oxidative burst was observed immediately after stimulation and was most likely due to an NAD(P)H oxidase. Experiments using selective pharmacological inhibitors demonstrated that activation of tyrosine kinases and phosphatidylinositol-3-kinase is required for induction of the oxidative burst. Blockade of the oxidative burst by diphenyleneiodonium impaired the release of preformed granular mediators, such as histamine and {beta}-hexosaminidase, and the secretion of newly synthesized leukotriene C4, whereas selective scavenging H2O2 by ebselen impaired leukotriene C4 secretion, but not degranulation. Sustained elevation of cytosolic calcium through store-operated calcium entry was totally abolished when ROS production was blocked. In contrast, selective depletion of H2O2 caused a considerable decrease and delay of the calcium response. Finally, tyrosine phosphorylation of phospholipase C{gamma} and the linker for activation of T cells, an event required for calcium influx, was suppressed by diphenyleneiodonium and ebselen. These studies demonstrate that activation of the intracellular oxidative burst is an important regulatory mechanism of mast cell responses.




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