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Dexamethasone and FK506 Inhibit Expression of Distinct Subsets of Chemokines in Human Mast Cells¹

Atsushi Kato^*,, Regina T. Chustz^*, Takahisa Ogasawara, Marianna Kulka^*, Hirohisa Saito, Robert P. Schleimer^* and Kenji Matsumoto^2,

^* Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan

Mast cells produce a large amount of several chemokines after cross-linking of FcRI and participate in the pathogenesis of allergic diseases. The objective of this study was to comprehensively investigate FcRI-mediated chemokine induction in human mast cells and the effect of a corticosteroid (dexamethasone) and a calcineurin inhibitor (FK506). Human peripheral blood-derived mast cells were stimulated with anti-IgE Ab in the presence of dexamethasone or FK506. Gene expression profiles were evaluated using GeneChip and confirmed by real-time PCR, and chemokine concentrations were measured by cytometric bead arrays and ELISA. Expression of eight chemokines was significantly induced in mast cells by anti-IgE stimulation. Induction of CCL2, CCL7, CXCL3, and CXCL8 by anti-IgE was significantly inhibited by dexamethasone but was enhanced by FK506. In contrast, induction of CCL1, CCL3, CCL4, and CCL18 was significantly inhibited by FK506 but, with the exception of CCL1, was enhanced by dexamethasone. Combination of dexamethasone and FK506 suppressed production of all chemokines by anti-IgE stimulation. Studies using protease inhibitors indicate that mast cell proteases may degrade several of the chemokines. These results suggest that corticosteroids and calcineurin inhibitors inhibit expression of distinct subsets of chemokines, and a combination of these drugs almost completely suppresses the induction of all chemokine genes in human mast cells in response to FcRI-dependent stimulation. This implies that a combination of a corticosteroid and a calcineurin inhibitor may be more effective than each single agent for the treatment of allergic diseases in which mast cell-derived chemokines play a major role.

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 in part by grants from the National Institute of Biomedical Innovation (ID05-24 and ID05-41), the Japan Health Science Foundation (KH51046), and the National Institutes of Health (R01 HL068546).

² Address correspondence and reprint requests to Dr. Kenji Matsumoto, Department of Allergy and Immunology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku 157-8535, Tokyo, Japan. E-mail address: kmatsumoto{at}nch.go.jp

³ Abbreviations used in this paper: PG, prostaglandin; CBA, cytometric bead array; DEX, dexamethasone; FK506, tacrolimus; GR, glucocorticoid receptor; GRE, glucocorticoid response element; LT, leukotriene; PIC, protease inhibitor cocktail; SCF, stem cell factor.