Cysteinyl Leukotrienes and Uridine Diphosphate Induce Cytokine Generation by Human Mast Cells Through an Interleukin 4-regulated Pathway that Is Inhibited by Leukotriene Receptor Antagonists

doi:10.1084/jem.20020044

Published 4 March 2002. doi:10.1084/jem.20020044

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© Rockefeller University Press, 0022-1007/2002/3/583/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 5, March 4, 2002 583-592

Original Article

Cysteinyl Leukotrienes and Uridine Diphosphate Induce Cytokine Generation by Human Mast Cells Through an Interleukin 4–regulated Pathway that Is Inhibited by Leukotriene Receptor Antagonists

Elizabeth A. Mellor¹, K. Frank Austen¹^,2^,4 and Joshua A. Boyce¹^,2^,3^,4

¹ Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital
² Department of Medicine, Harvard Medical School
³ Department Pediatrics, Harvard Medical School
⁴ Partners Asthma Center, Boston, MA 02115

Address correspondence to Joshua A. Boyce, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Smith Research Building, One Jimmy Fund Way, Boston, MA 02115. Phone: 617-525-1233; Fax: 617-525-1310; E-mail: jboyce{at}rics.bwh.harvard.edu

We previously reported that interleukin (IL)-4 upregulates theexpression of leukotriene C₄ synthase (LTC₄S) by human cordblood–derived mast cells (hMCs), augments their high-affinityFc receptor for IgE (Fc ${epsilon}$ RI)-dependent generation of eicosanoidsand cytokines, and induces a calcium flux in response to cysteinylleukotrienes (cys-LTs) and uridine diphosphate (UDP) that isblocked by cys-LT receptor antagonists. We speculated that thisIL-4–dependent, receptor-mediated response to the cys-LTsand UDP might induce cytokine generation by hMCs without concomitantexocytosis. Unlike hMCs maintained in cytoprotective stem cellfactor (SCF) alone, hMCs primed for 5 d with IL-4 respondedto UDP (1 µM), LTC₄ (100 nM), and LTD₄ (100 nM) by producingIL-5, tumor necrosis factor (TNF)- ${alpha}$ , and especially large quantitiesof macrophage inflammatory protein (MIP)-1ß de novoat 6 h, preceded by the induced expression of the correspondingmRNAs. Cys-LT– and UDP-mediated cytokine production bythe primed hMCs occurred without histamine release or PGD₂ generationand was inhibited by the CysLT1 receptor antagonist MK571. Additionally,pretreatment of hMCs with MK571 or with the cys-LT biosyntheticinhibitor MK886 decreased IL-5 and TNF- ${alpha}$ production in responseto IgE receptor cross-linkage, implying a positive feedbackby endogenously produced cys-LTs. Cys-LTs and UDP thus orchestratea novel, IL-4–regulated, non-IgE–dependent hMC activationfor cytokine gene induction that could be initiated by microbes,cellular injury, or neurogenic or inflammatory signals; andthis pathobiologic event would not be recognized in tissue studieswhere hMC activation is classically defined by exocytosis.

Key Words: mast cells • cytokines • leukotrienes • uridine diphosphate • receptors

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