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Am. J. Respir. Crit. Care Med., Volume 164, Number 11, December 2001, 2098-2101

Interferon-gamma Modulates Cysteinyl Leukotriene Receptor-1 Expression and Function in Human Airway Myocytes

YASSINE AMRANI, PAUL E. MOORE, REBECCA HOFFMAN, STEPHANIE A. SHORE, and REYNOLD A. PANETTIERI JR.

Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and Physiology Program, Harvard School of Public Health, Boston, Massachusetts

Leukotrienes play a critical role in promoting bronchoconstriction in asthma. The purpose of this study was to examine whether interferon (IFN)-gamma , a cytokine upregulated in asthmatic airways, modulates leukotriene (LT)D4 receptor expression and contractile responses in cultured human airway smooth muscle (HASM) cells. Treatment of HASM cells with IFN-gamma (10 to 1,000 U/ml) stimulated a dose-dependent increase in cell-surface expression of cysteinyl leukotriene receptor 1 (CysLT1) as determined by flow cytometry. CysLT1 messenger RNA (mRNA) levels were also significantly enhanced by IFN-gamma , as demonstrated by reverse transcription-polymerase chain reaction. To determine the functional relevance of increased CysLT1 expression in HASM, cell stiffness responses to LTD4 were measured with magnetic twisting cytometry. IFN-gamma (1,000 U/ml for 24 h) markedly increased LTD4-induced changes in cell stiffness, from 4.6 ± 1 [mean ± SEM]% to 24.4 ± 3.7% (n = 8, p < 0.05). Montelukast, a CysLT1 antagonist, completely inhibited LTD4-induced increases in cell stiffness. IFN-gamma had no effect on the cell stiffness responses to bradykinin, another contractile agonist. Collectively, these data suggest that IFN-gamma increases LTD4 responses in HASM cells by increasing cell-surface expression of CysLT1. Our data suggest that increased levels of IFN-gamma in asthmatic individuals may promote airway hyperresponsiveness and asthma exacerbations by directly modulating contractile responses of HASM.




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Copyright © 2001 American Thoracic Society