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

Am J Respir Crit Care Med. 2001 Dec 1;164(11):2098-101. doi: 10.1164/ajrccm.164.11.2108005.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetates / pharmacology
  • Asthma / immunology*
  • Asthma / metabolism*
  • Asthma / physiopathology
  • Bradykinin / pharmacology
  • Cells, Cultured
  • Constriction, Pathologic
  • Cytoskeleton / immunology
  • Cytoskeleton / physiology
  • Dose-Response Relationship, Drug
  • Flow Cytometry
  • Humans
  • Interferon-gamma / immunology*
  • Interferon-gamma / metabolism*
  • Leukotriene Antagonists
  • Membrane Proteins*
  • Muscle, Smooth* / cytology
  • Muscle, Smooth* / immunology
  • Muscle, Smooth* / metabolism
  • Muscle, Smooth* / physiopathology
  • Pliability
  • Quinolines / pharmacology
  • Receptors, Leukotriene / immunology*
  • Receptors, Leukotriene / metabolism*
  • Respiratory Muscles* / cytology
  • Respiratory Muscles* / immunology
  • Respiratory Muscles* / metabolism
  • Respiratory Muscles* / physiopathology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Up-Regulation

Substances

  • Acetates
  • Leukotriene Antagonists
  • Membrane Proteins
  • Quinolines
  • Receptors, Leukotriene
  • Interferon-gamma
  • cysteinyl leukotriene receptor 2
  • leukotriene D4 receptor
  • montelukast
  • Bradykinin