Montelukast, a cysteinyl-leukotriene receptor (CysLT-R) antagonist, has anti-inflammatory activity in the treatment of allergic diseases. If this effect is due only to blocking leukotrienes or also to inhibiting proliferation and survival of inflammatory cells, is actually unknown. We tested the hypothesis that Montelukast could influence T lymphocyte functional behaviour in vitro.
Normal T cells were analyzed for surface expression of CysLT-R1 and R2 at resting and after activation with Th2-type cytokines or T-cell receptor (TcR) stimulation. Proliferation, as well as IL-4 and IFN-γ production, were determined in samples exposed to 10-8 to 10-5 M of Montelukast . Apoptosis was evaluated by propidium iodide and anti-Annexin V mAb staining. cDNA microarray technique was adopted to identify gene products involved in apoptosis induction.
Resting T cells expressed low levels of CysLT receptors. Upon anti-CD3 activation, a progressive increase in CysLT-R1 and R2 expression was observed. Exposure to Montelukast reduced proliferative response to TcR engagement, increased IFN-γ production and led to apoptosis at minimal concentrations of 10-6 M. A progressive loss in BAD and Bcl-2 activities, and an increase in the expression of CD27, TRAF3, TRAIL, p53 and Fas genes were also observed.
Biological effects of Montelukast delineate a complex picture of gene activation and repression, probably induced by CysLT-R blockade. The induction of apoptosis in allergen-specific T-cell population, as a final result, appears fundamental in the treatment of asthma.