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

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.