Am. J. Respir. Cell Mol. Biol., Volume 25, Number 1, July, 2001 92-97

Geldanamycin Inhibits NF-B Activation and Interleukin-8 Gene Expression in Cultured Human Respiratory Epithelium

Vivek Malhotra, Thomas P. Shanley, Jean-Francois Pittet, William J. Welch, and Hector R. Wong

Division of Critical Care Medicine, Children's Hospital Medical Center and Children's Hospital Research Foundation, Cincinnati, Ohio; and Departments of Anesthesia and Surgery, University of California San Francisco, San Francisco, California

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)-B activation. Geldanamycin inhibited tumor necrosis factor (TNF)--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--mediated luciferase activity. Geldanamycin inhibited TNF--mediated NF-B activation as measured by electromobility shift assays and transient transfections with a NF-B-dependent luciferase reporter plasmid. In contrast, geldanamycin did not affect TNF--mediated degradation of the NF-B inhibitory protein IB and did not block nuclear translocation of the NF-B p65 subunit as measured by Western blot analyses. Geldanamycin added directly to nuclear extracts of TNF--treated cells reduced the formation of the NF-B/DNA complex. These results demonstrate that geldanamycin inhibits TNF--mediated IL-8 gene expression in A549 cells by inhibiting activation of the IL-8 promoter. The mechanism of inhibition involves inhibition of NF-B activation, which is independent of IB degradation or p65 nuclear translocation. Geldanamycin appears to directly inhibit the ability of NF-B to bind DNA. The observed in vitro effects could account, in part, for the anti-inflammatory properties of geldanamycin observed in vivo.

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