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J. Biol. Chem., Vol. 279, Issue 47, 48751-48759, November 19, 2004

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Rodent and Human Mast Cells Produce Functionally Significant Intracellular Reactive Oxygen Species but Not Nitric Oxide^*

Emily J. Swindle¶, Dean D. Metcalfe, and John W. Coleman

From the Department of Pharmacology, University of Liverpool, Liverpool L69 3GE, United Kingdom and the Laboratory of Allergic Diseases, NIAID, National Institutes of Health, Bethesda, Maryland 20892

In immunity, reactive oxygen species (ROS) and nitric oxide (NO) are important antimicrobial agents and regulators of cell signaling and activation pathways. However, the cellular sources of ROS and NO are much debated. Particularly, there is contention over whether mast cells, key secretory cells in allergy and immunity, can generate these chemical species, and if so, whether they are of functional significance. We therefore examined directly by flow cytometry the capacity of mast cells to generate intracellular ROS and NO using the respective cell-permeable fluorescent probes dichlorodihydrofluorescein and diaminofluorescein and evaluated the effects of inhibitors of ROS and NO synthesis on cell degranulation. For each of three mast cell types (rat peritoneal mast cells, mouse bone marrow-derived mast cells, and human blood-derived mast cells), degranulation stimulated by IgE/antigen was accompanied by production of intracellular ROS but not NO. Inhibition of ROS production led to reduced degranulation, indicating a facilitatory role for ROS, whereas NO synthase inhibitors were without effect. Likewise, bacterial lipopolysaccharide and interferon- over a wide range of conditions failed to generate intracellular NO in mast cells, whereas these agents readily induced intracellular NO in macrophages. NO synthase protein, as assessed by Western blotting, was readily induced in macrophages but not mast cells. We conclude that rodent and human mast cells generate intracellular ROS but not NO and that intracellular ROS but not intracellular NO are functionally linked to mast cell degranulation.

Received for publication, August 24, 2004

^* This work was supported by a grant (to J. W. C.) from The Wellcome Trust and by National Institutes of Health intramural funds. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Laboratory of Allergic Diseases, NIAID, National Institutes of Health, Bldg. 10, Rm. 11C 209, Bethesda, MD 20892-1881. Tel.: 301-594-1276; Fax: 301-480-8384; E-mail: ejswindle{at}niaid.nih.gov.

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