Interferon-gamma 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)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.
Amrani
Y
Y
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160, USA.
Moore
P E
PE
Hoffman
R
R
Shore
S A
SA
Panettieri
R A
RA
D000085:Acetates / Q000494:pharmacology; D001249:Asthma / Q000276:immunology* / Q000378:metabolism* / Q000503:physiopathology; D001920:Bradykinin / Q000494:pharmacology; D002478:Cells, Cultured; D003251:Constriction, Pathologic; D003521:Cyclopropanes; D003599:Cytoskeleton / Q000276:immunology / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism*; D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D009130:Muscle, Smooth / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D018583:Pliability; D011804:Quinolines / Q000494:pharmacology; D018077:Receptors, Leukotriene / Q000276:immunology* / Q000378:metabolism*; D012132:Respiratory Muscles / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013440:Sulfides; D015854:Up-Regulation
D000085:Acetates; D003521:Cyclopropanes; D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D011804:Quinolines; D018077:Receptors, Leukotriene; D013440:Sulfides; D007371:Interferon-gamma; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor; C093875:montelukast; D001920:Bradykinin