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Published ahead of print on June 10, 2004, doi:10.1165/rcmb.2004-0089OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 31, pp. 283-291, 2004
© 2004 American Thoracic Society
DOI: 10.1165/rcmb.2004-0089OC

Molecular Regulation of Interleukin-13 and Monocyte Chemoattractant Protein-1 Expression in Human Mast Cells by Interleukin-1ß

Steven A. Lee, S. Matthew Fitzgerald, Shau K. Huang, Chuanfu Li, David S. Chi, Denise M. Milhorn and Guha Krishnaswamy

Departments of Internal Medicine and Surgery, East Tennessee State University, Johnson City, Tennessee; and the Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland

Address correspondence to: Guha Krishnaswamy, M.D., F.A.C.P., F.C.C.P., Department of Internal Medicine, Division of Allergy and Clinical Immunology, P.O. Box 70622, Johnson City, TN 37614-1709. E-mail: krishnas{at}etsu.edu

Mast cells play pivotal roles in immunoglobulin (Ig) E–mediated airway inflammation, expressing interleukin (IL)-13 and monocyte chemoattractant protein-1 (MCP-1), which in turn regulate IgE synthesis and/or inflammatory cell recruitment. The molecular effects of IL-1ß on cytokine expression by human mast cells (HMC) have not been studied well. In this report, we provide evidence that human umbilical cord blood-derived mast cells (CBDMC) and HMC-1 cells express the type 1 receptor for IL-1. We also demonstrate that IL-1ß and tumor necrosis factor-{alpha} are able to induce, individually or additively, dose-dependent expression of IL-13 and MCP-1 in these cells. The induction of IL-13 and MCP-1 gene expression by IL-1ß was accompanied by the activation of IL-1 receptor–associated kinase and translocation of the transcription factor, nuclear factor (NF) {kappa}B into the nucleus. Accordingly, Bay-11 7082, an inhibitor of NF-{kappa}B activation, inhibited IL-1ß–induced IL-13 and MCP-1 expression. IL-1ß also induced IL-13 promoter activity while enhancing the stability of IL-13 messenger RNA transcripts. Dexamethasone, a glucocorticoid, inhibited IL-1ß–induced nuclear translocation of NF-{kappa}B and also the secretion of IL-13 from mast cells. Our data suggest that IL-1ß can serve as a pivotal costimulus of inflammatory cytokine synthesis in human mast cells, and this may be partly mediated by IL-1 receptor–binding and subsequent signaling via nuclear translocation of NF-{kappa}B. Because IL-1ß is a ubiquitously expressed cytokine, these findings have important implications for non–IgE-mediated signaling in airway mast cells as well as for innate immunity and airway inflammatory responses, such as observed in extrinsic and intrinsic asthma.

Abbreviations: cord blood–derived mast cells, CBDMC • ethylenediaminetetraacetic acid, EDTA • enzyme-linked immunosorbent assay, ELISA • electrophoretic mobility shift assay, EMSA • Fc epsilon receptor I, Fc{epsilon}RI • immunoglobulin, Ig • interleukin, IL • IL-1 receptor–associated kinase, IRAK • IL-1 receptor type 1, IL-1RI • monocyte chemoattractant protein-1, MCP-1 • nuclear factor-{kappa}B, NF-{kappa}B • phosphate-buffered saline, PBS • phorbol 12-myristate 13-acetate, PMA • PMA/ionomycin, PMA/iono • reverse transcriptase–polymerase chain reaction, RT-PCR




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