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FcRI- and Fc Receptor-Mediated Production of Reactive Oxygen Species by Mast Cells Is Lipoxygenase- and Cyclooxygenase-Dependent and NADPH Oxidase-Independent¹

Emily J. Swindle^2,*, John W. Coleman^*, Frank R. DeLeo and Dean D. Metcalfe^*

^* Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1881; and Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840

We investigated the enzymes responsible for FcRI-dependent production of reactive oxygen species (ROS) and the influence of ROS on mast cell secretory responses. 5-Lipoxygenase (5-LO) was the primary enzyme involved in ROS production by human mast cells (huMC) and mouse bone marrow-derived mast cells (mBMMC) following FcRI aggregation because incubation with 5-LO inhibitors (AA861, nordihydroguaiaretic acid, zileuton) but not a flavoenzyme inhibitor (diphenyleneiodonium) completely abrogated Ag-induced dichlorodihydrofluorescein (DCF) fluorescence. Furthermore, 5-LO-deficient mBMMC had greatly reduced FcRI-dependent DCF fluorescence compared with wild type mBMMC or those lacking a functional NADPH oxidase (i.e., gp91^phox- or p47^phox-deficient cells). A minor role for cyclooxygenase (COX)-1 in FcRI-dependent ROS production was demonstrated by inhibition of Ag-mediated DCF fluorescence by a COX-1 inhibitor (FR122047) and reduced DCF fluorescence in COX-1-deficient mBMMC. Complete abrogation of FcRI-dependent ROS production in mast cells had no effect on degranulation or cytokine secretion. In response to the NADPH oxidase-stimulating agents including PMA, mBMMC and huMC produced negligible ROS. IgG-coated latex beads did stimulate ROS production in huMC, and in this experiment 5-LO and COX again appeared to be the enzymatic sources of ROS. In contrast, IgG-coated latex bead-induced ROS production in human polymorphonuclear leukocytes occurred by the NADPH oxidase pathway. Thus mBMMC and huMC generate ROS by 5-LO and COX-1 in response to FcRI aggregation; huMC generate ROS upon exposure to IgG-coated latex beads by 5-LO and COX; and ROS appear to have no significant role in FcRI-dependent degranulation and cytokine production.

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.

¹ This work was supported by National Institutes of Health intramural funds.

² Address correspondence and reprint requests Dr. Emily J. Swindle, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 11C 209, 10 Center Drive MSC 1881, Bethesda, MD 20892-1881. E-mail address: ejswindle{at}niaid.nih.gov

³ Abbreviations used in this paper: ROS, reactive oxygen species; AUC, area under the curve; COX, cyclooxygenase; mBMMC, mouse bone marrow-derived mast cell; PMN, polymorphonuclear leukocyte; LT, leukotriene; DCF, dichlorofluorescein; HSA, human serum albumin; DPI, diphenyleneiodonium; huMC, human mast cell; 5-LO, 5-lipoxygenase; DHE, dihydroethidium; DHR, dihydrorhodamine; IgG-LB, IgG-coated latex bead; PHGP, phospholipid hydroperoxide glutathione peroxidase; WT, wild type.

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