Interferon-γ modulates cysteinyl leukotriene receptor-1 expression and function in human airway myocytes

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)D-4 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 (CysLT(1)) as determined by flow cytometry, CysLT(1) 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 CysLT(1) 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 CysLT(1) 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 CysLT(1). 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.