Montelukast inhibits tumour necrosis factor-alpha-mediated interleukin-8 expression through inhibition of nuclear factor-kappa B p65-associated histone acetyltransferase activity
Articolo
Data di Pubblicazione:
2008
Citazione:
Montelukast inhibits tumour necrosis factor-alpha-mediated interleukin-8 expression through inhibition of nuclear factor-kappa B p65-associated histone acetyltransferase activity / F. Tahan, E. Jazrawi, T. Moodley, G. Rovati, I.M. Adcock. - In: CLINICAL AND EXPERIMENTAL ALLERGY. - ISSN 0954-7894. - 38:5(2008), pp. 805-811.
Abstract:
Montelukast is a potent cysteinyl leukotriene-1 receptor antagonist
possessing some anti-inflammatory effects although the molecular mechanism of
these anti-inflammatory effects is unknown. In this study, we aimed to
investigate the effect of montelukast on nuclear factor (NF)-kappaB-associated
histone acetylation activity in phorbol myristate acetate (PMA)-differentiated
U937 cells. METHODS: We examined the inhibitory effects of montelukast on
TNF-alpha-induced IL-8 production in PMA-differentiated U-937 cells. U-937 cells
were exposed to PMA (50 ng/mL) for 48 h to allow differentiation to macrophages.
Macrophages were then exposed to TNF-alpha (10 ng/mL) in the presence or absence
of montelukast (0.01-10 microm) for 24 h. After this time, the concentration of
IL-8 in the culture supernatant was measured by sandwich-type ELISA kit. The
effect of signalling pathways on TNF-alpha-induced IL-8 release was examined
pharmacologically using selective NF-kappaB/IKK2 (AS602868, 3 microm), (PD98059,
10 microm) and p38 mitogen activated protein kinase (MAPK) (SB203580, 1 microm)
inhibitors. NF-kappaB DNA binding activity was measured by a DNA-binding
ELISA-based assay. NF-kappaB-p65-associated histone acetyltransferase (HAT)
activity was measured by immunoprecipitation linked to commercial fluorescent
HAT. RESULTS: TNF-alpha-induced IL-8 release was suppressed by an NF-kappaB
inhibitor but not by MEK or p38 MAPK inhibitors. Montelukast induced a
concentration-dependent inhibition of TNF-alpha-induced IL-8 release and mRNA
expression that reached a plateau at 0.1 microm without affecting cell viability.
Montelukast did not affect NF-kappaB p65 activation as measured by DNA binding
but suppressed NF-kappaB p65-associated HAT activity. CONCLUSION: Montelukast
inhibits TNF-alpha-stimulated IL-8 expression through changes in NF-kappaB
p65-associated HAT activity. Drugs targeting these enzymes may enhance the
anti-inflammatory actions of montelukast.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
histone acetylase ; IL-8 ; macrophages ; montelukast ; NF-κB
Elenco autori:
F. Tahan, E. Jazrawi, T. Moodley, G. Rovati, I.M. Adcock
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