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Geldanamycin inhibits NF-kappaB activation and interleukin-8 gene expression in cultured human respiratory epithelium.

Abstract：

:Geldanamycin is a benzoquinone ansamycin with multiple pharmacologic properties. Recent data demonstrated that geldanamycin conferred protection in an animal model of inflammation-associated acute lung injury. In the current study, we investigated the effects of geldanamycin on interleukin (IL)-8 gene expression and nuclear factor (NF)-kappaB activation. Geldanamycin inhibited tumor necrosis factor (TNF)-alpha-mediated IL-8 gene expression in A549 human respiratory epithelial cells as measured by enzyme-linked immunosorbent assay and Northern blot analyses. In cells transiently transfected with an IL-8 promoter-luciferase reporter plasmid, geldanamycin inhibited TNF-alpha-mediated luciferase activity. Geldanamycin inhibited TNF-alpha-mediated NF-kappaB activation as measured by electromobility shift assays and transient transfections with a NF-kappaB-dependent luciferase reporter plasmid. In contrast, geldanamycin did not affect TNF-alpha-mediated degradation of the NF-kappaB inhibitory protein IkappaBalpha and did not block nuclear translocation of the NF-kappaB p65 subunit as measured by Western blot analyses. Geldanamycin added directly to nuclear extracts of TNF-alpha-treated cells reduced the formation of the NF-kappaB/DNA complex. These results demonstrate that geldanamycin inhibits TNF-alpha-mediated IL-8 gene expression in A549 cells by inhibiting activation of the IL-8 promoter. The mechanism of inhibition involves inhibition of NF-kappaB activation, which is independent of IkappaBalpha degradation or p65 nuclear translocation. Geldanamycin appears to directly inhibit the ability of NF-kappaB to bind DNA. The observed in vitro effects could account, in part, for the anti-inflammatory properties of geldanamycin observed in vivo.

journal_name

Am J Respir Cell Mol Biol

journal_title

American journal of respiratory cell and molecular biology

authors

Malhotra V,Shanley TP,Pittet JF,Welch WJ,Wong HR

doi

10.1165/ajrcmb.25.1.4384

keywords:

subject

Has Abstract

pub_date

2001-07-01 00:00:00

pages

92-7

issue

eissn

1044-1549

issn

1535-4989

journal_volume

pub_type

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Geldanamycin inhibits NF-kappaB activation and interleukin-8 gene expression in cultured human respiratory epithelium.