CysLT1 receptor upregulation by TGF-beta and IL-13 is associated with bronchial smooth muscle cell proliferation in response to LTD4

J Allergy Clin Immunol. 2003 May;111(5):1032-40. doi: 10.1067/mai.2003.1451.


Background: Airway remodeling is a feature of chronic asthma. It involves a number of structural changes, including bronchial smooth muscle cell (BSMC) hyperplasia and hypertrophy. Cysteinyl leukotrienes (cysLTs) have been suggested to play a role in airway remodeling in addition to their numerous other physiopathologic effects.

Objectives: This work was aimed at characterizing the potential modulation of CysLT1 receptor expression by cytokines and the eventual functional relevance of this modulation.

Methods: Expression of CysLT1 receptor was measured by flow cytometry and immunofluorescence microscopy. Transcripts were measured by RT-PCR and BSMC proliferation by crystal violet staining.

Results: When human BSMC were exposed to transforming growth factor (TGF)-beta, IL-13, or IFN-gamma, their expression of CysLT1 receptor was significantly augmented in a time- and concentration-dependent manner. Interestingly, IL-4 had no significant effect on CysLT1 receptor expression in BSMC. Moreover, IL-13 and IFN-gamma but not TGF-beta were able to increase CysLT1 mRNA levels. Finally, when BSMC were pretreated with TGF-beta or IL-13 but not IFN-gamma, their responsiveness to LTD(4) was markedly enhanced in terms of BSMC proliferation. Whereas TGF-beta, IL-13, or LTD(4) alone had little effect on BSMC proliferation, preexposure of the cells to TGF-beta or IL-13 for 24 hours resulted in a significant increase in proliferation in response to LTD(4). The enhanced proliferation was totally prevented by pretreating the cytokine-primed BSMC with the selective CysLT1 receptor antagonist Montelukast.

Conclusions: Taken together, our findings indicate a synergy between certain cytokines and cysLTs, mediated by the augmented expression of the CysLT1 receptor and subsequent LTD(4)-triggered BSMC proliferation. These findings support a role for cysLTs in the airway remodeling observed in asthmatic patients and may provide a rationale for preventive and therapeutic intervention.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bronchi / cytology*
  • Bronchi / drug effects
  • Bronchi / metabolism
  • Cell Division / drug effects
  • Cells, Cultured
  • Humans
  • Interferon-gamma / pharmacology
  • Interleukin-13 / pharmacology*
  • Interleukin-4 / pharmacology
  • Leukotriene D4 / pharmacology*
  • Membrane Proteins*
  • Muscle, Smooth / cytology
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / metabolism
  • RNA, Messenger / analysis
  • Receptors, Leukotriene / genetics
  • Receptors, Leukotriene / physiology*
  • Transforming Growth Factor beta / pharmacology*


  • Interleukin-13
  • Membrane Proteins
  • RNA, Messenger
  • Receptors, Leukotriene
  • Transforming Growth Factor beta
  • Interleukin-4
  • Leukotriene D4
  • Interferon-gamma
  • cysteinyl leukotriene receptor 2
  • leukotriene D4 receptor