Effect of montelukast on nuclear factor kappaB activation and proinflammatory molecules.
BACKGROUND
Montelukast is known as a cysteinyl leukotriene 1 receptor antagonist. However, the action of montelukast in terms of nuclear factor KB (NF-kappaB) activation and the production of proinflammatory molecules is unknown.


OBJECTIVE
To demonstrate the potential anti-inflammatory effect of montelukast.


METHODS
We examined whether montelukast inhibits the activation of NF-kappaB, a transcription factor that regulates the expression of proinflammatory molecules. The inhibitory effects of montelukast on tumor necrosis factor kappa (TNF-kappa)--induced NF-kappaB activation on THP-1 cells, a human monocytic leukemia cell line, were evaluated by flow cytometry, and those on lipopolysaccharide-induced interleukin 1beta (IL-1beta), IL-6, TNF-alpha, and monocyte chemoattractant protein 1 (MCP-1) production in peripheral blood mononuclear cells were evaluated by enzyme-linked immunosorbent assay.


RESULTS
Flow cytometry demonstrated that montelukast inhibited NF-kappaB activation in THP-1 cells in a dose-related manner. Furthermore, 10(-5)M montelukast significantly inhibited lipopolysaccharide-induced IL-6, TNF-alpha, and MCP-1 production in the peripheral blood mononuclear cells of controls and patients with asthma. Lipopolysaccharide-induced IL-1beta production was not inhibited by montelukast.


CONCLUSIONS
These findings suggest that high doses of montelukast modulate the production of IL-6, TNF-alpha, and MCP-1 through the inhibition of NF-kappaB activation. However, the anti-inflammatory effect of montelukast at therapeutic doses in patients with asthma needs to be further investigated.
Department of Pediatrics, Yamaguchi University School of Medicine, Yamaguchi, Japan.
Shinji
S
Maeba
Takashi
T
Ichiyama
Yoshiko
Y
Ueno
Haruyuki
H
Makata
Tomoyo
T
Matsubara
Susumu
S
Furukawa
D000085:Acetates / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000494:pharmacology*; D013440:Sulfides; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000085:Acetates; D000893:Anti-Inflammatory Agents; D018932:Chemokine CCL2; D003521:Cyclopropanes; D018836:Inflammation Mediators; D015850:Interleukin-6; D020024:Leukotriene Antagonists; D016328:NF-kappa B; D011804:Quinolines; D013440:Sulfides; D014409:Tumor Necrosis Factor-alpha; C093875:montelukast