Biological effects of montelukast, a cysteinyl-leukotriene receptor-antagonist, on T lymphocytes.
BACKGROUND
Montelukast (MNT), a cysteinyl-leukotriene receptor (Cys-LTR) antagonist, has anti-inflammatory activity in the treatment of allergic diseases. If this effect is due only to blocking leukotrienes or also owing to inhibiting proliferation and survival of inflammatory cells, is actually unknown.


OBJECTIVE
Testing the hypothesis that MNT could influence T lymphocyte functional behaviour in vitro.


METHODS
Normal T lymphocytes were analysed for surface expression of Cys-LTR(1) and Cys-LTR(2) by means of monoclonal antibodies (mAbs), in the resting state and after activation with T helper type 2 cytokine or T cell receptor (TcR) stimulation. Proliferative activity, as well as IL-4 andIFN-gamma production, were simultaneously determined in samples exposed to molar concentrations of MNT from 10(-8) to 10(-5). Programmed cell death in cultured samples was evaluated by means of propidium iodide and fluorescein isothiocyanate-conjugated anti-Annexin V mAb staining. The complementary DNA microarray technique was adopted to identify gene products involved in apoptosis induction.


RESULTS
Resting T cells expressed low levels of Cys-LTR. Upon anti-CD3 mAb activation, a progressive increase in Cys-LTR(1) and -LTR(2) expression was observed. Exposure to MNT reduced proliferative response to TcR engagement, increased IFN-gamma production and led to apoptosis at minimal concentrations of 10(-6) M. A progressive loss in BAD and B cell lymphoma/leukaemia-2 activities, and an increase in the expression of CD27, TRAF3, TRAIL, p53 and Fas genes were also observed.


CONCLUSIONS
Biological effects of MNT delineate a complex picture of gene activation and repression, probably induced by Cys-LTR blockade. The induction of apoptosis in allergen-specific T cell population, as a final result, appears fundamental in the treatment of asthma.
Spinozzi
F
F
Laboratory of Experimental Immunology and Allergy, Department of Clinical and Experimental Medicine, University of Perugia, I-06122 Perugia, Italy. spinozzi@unipg.it
Russano
A M
AM
Piattoni
S
S
Agea
E
E
Bistoni
O
O
de Benedictis
D
D
de Benedictis
F M
FM
D000085:Acetates / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002999:Clone Cells; D003521:Cyclopropanes; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects; D008565:Membrane Proteins / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011804:Quinolines / Q000494:pharmacology*; D018077:Receptors, Leukotriene / Q000032:analysis / Q000235:genetics; D013440:Sulfides; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D015533:Transcriptional Activation
D000085:Acetates; D000893:Anti-Inflammatory Agents; D003521:Cyclopropanes; D008565:Membrane Proteins; D011804:Quinolines; D018077:Receptors, Leukotriene; D013440:Sulfides; D015847:Interleukin-4; D007371:Interferon-gamma; C083169:leukotriene D4 receptor; C093875:montelukast