Montelukast inhibits TNFalpha-mediated IL-8 expression through inhibition of NF-kappa B p65-associated histone acetyltransferase activity
Abstract
Data di Pubblicazione:
2008
Citazione:
Montelukast inhibits TNFalpha-mediated IL-8 expression through inhibition of NF-kappa B p65-associated histone acetyltransferase activity / F. Tahan, E. Jazrawi, T. Moodley, G. Rovati, I. Adcock. - In: ALLERGY. - ISSN 0105-4538. - 63:suppl. 88(2008), pp. 605-605. ((Intervento presentato al 27. convegno EAACI Congress of the European Academy of Allergology and Clinical Immunology tenutosi a Barcelona nel 2008.
Abstract:
Background: Montelukast is a potent cysteinyl
leukotriene 1 receptor antagonist possessing
some anti-inflammatory effects
although the molecular mechanism of these
antiinflammatory effects are unknown. In
this study, we aimed to investigate the effect
of montelukast on NF-kB-associated histone
acetylation activity in PMA-differentiated
U937 cells.
Methods: We examined the inhibitory effects
of montelukast on TNF-a-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-a (10 ng/mL) in the presence
or absence of montelukast (0.01–
10 mM) for 24 h. After this time the concentration
of IL-8 in the culture supernatant
was measured by sandwich-type enzymelinked
immunosorbent assay (ELISA) kit.
The effect of signalling pathways on TNF-ainduced
IL-8 release was examined pharmacologically
using selective NF-kB/IKK2
(AS602868, 3 mM), MEK (PD98059,
10 mM) and p38 MAPK (SB203580, 1 mM)
inhibitors. NF-kB DNA binding activity
was measured by a DNA-binding ELISAbased
assay. NF-kB-p65-associated histone
acetyltransferase (HAT) activity was measured
by immunoprecipitation linked to
commercial flourescent HAT.
Results: TNFa-induced IL-8 release was
suppressed by an NF-kB inhibitor but not
by MEK or p38 MAPK inhibitors. Montelukast
induced a concentration-dependent
inhibition of TNFa-induced IL-8 release
and mRNA expression which reached a plateau at 0.1 mM without affecting cell
viability. Montelukast did not affect NFkB
p65 activation as measured by DNA
binding but suppressed NF-kB p65-associated
HAT activity.
Conclusion: Montelukast inhibits TNFa-stimulated IL-8 expression through changes in NF-kB p65-associated HAT activity. Drugs targetting 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. Adcock
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