Secretory leucoprotease inhibitor (SLPI) is a nonglycosylated protein produced by epithelial cells. In addition to its antiprotease activity, SLPI has been shown to exhibit antiinflammatory properties, including down-regulation of tumor necrosis factor α expression by lipopolysaccharide (LPS) in macrophages and inhibition of nuclear factor (NF)-κB activation in a rat model of acute lung injury. We have previously shown that SLPI can inhibit LPS-induced NF-κB activation in monocytic cells by inhibiting degradation of IκBα without affecting the LPS-induced phosphorylation and ubiquitination of IκBα. Here, we present evidence to show that upon incubation with peripheral blood monocytes (PBMs) and the U937 monocytic cell line, SLPI enters the cells, becoming rapidly localized to the cytoplasm and nucleus, and affects NF-κB activation by binding directly to NF-κB binding sites in a site-specific manner. SLPI can also prevent p65 interaction with the NF-κB consensus region at concentrations commensurate with the physiological nuclear levels of SLPI and p65. We also demonstrate the presence of SLPI in nuclear fractions of PBMs and alveolar macrophages from individuals with cystic fibrosis and community-acquired pneumonia. Therefore, SLPI inhibition of NF-κB activation is mediated, in part, by competitive binding to the NF-κB consensus-binding site.
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19 December 2005
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December 13 2005
Secretory leucoprotease inhibitor binds to NF-κB binding sites in monocytes and inhibits p65 binding
Clifford C. Taggart,
Clifford C. Taggart
1Pulmonary Research Division, Department of Medicine, Education and Research Centre, Beaumont Hospital
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Sally-Ann Cryan,
Sally-Ann Cryan
2School of Pharmacy, Royal College of Surgeons in Ireland, Dublin 2, Ireland
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Sinead Weldon,
Sinead Weldon
1Pulmonary Research Division, Department of Medicine, Education and Research Centre, Beaumont Hospital
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Aileen Gibbons,
Aileen Gibbons
2School of Pharmacy, Royal College of Surgeons in Ireland, Dublin 2, Ireland
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Catherine M. Greene,
Catherine M. Greene
1Pulmonary Research Division, Department of Medicine, Education and Research Centre, Beaumont Hospital
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Emer Kelly,
Emer Kelly
1Pulmonary Research Division, Department of Medicine, Education and Research Centre, Beaumont Hospital
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Teck Boon Low,
Teck Boon Low
1Pulmonary Research Division, Department of Medicine, Education and Research Centre, Beaumont Hospital
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Shane J. O'Neill,
Shane J. O'Neill
1Pulmonary Research Division, Department of Medicine, Education and Research Centre, Beaumont Hospital
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Noel G. McElvaney
Noel G. McElvaney
1Pulmonary Research Division, Department of Medicine, Education and Research Centre, Beaumont Hospital
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Clifford C. Taggart
1Pulmonary Research Division, Department of Medicine, Education and Research Centre, Beaumont Hospital
Sally-Ann Cryan
2School of Pharmacy, Royal College of Surgeons in Ireland, Dublin 2, Ireland
Sinead Weldon
1Pulmonary Research Division, Department of Medicine, Education and Research Centre, Beaumont Hospital
Aileen Gibbons
2School of Pharmacy, Royal College of Surgeons in Ireland, Dublin 2, Ireland
Catherine M. Greene
1Pulmonary Research Division, Department of Medicine, Education and Research Centre, Beaumont Hospital
Emer Kelly
1Pulmonary Research Division, Department of Medicine, Education and Research Centre, Beaumont Hospital
Teck Boon Low
1Pulmonary Research Division, Department of Medicine, Education and Research Centre, Beaumont Hospital
Shane J. O'Neill
1Pulmonary Research Division, Department of Medicine, Education and Research Centre, Beaumont Hospital
Noel G. McElvaney
1Pulmonary Research Division, Department of Medicine, Education and Research Centre, Beaumont Hospital
CORRESPONDENCE Clifford C. Taggart: [email protected]
Abbreviations used: AM, alveolar macrophage; ChIP, chromatin immunoprecipitation; EMSA, electromobility shift assay; LTA, lipoteichoic acid; PBM, peripheral blood monocyte; SLPI, secretory leucoprotease inhibitor.
Received:
April 15 2005
Accepted:
November 03 2005
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2005
J Exp Med (2005) 202 (12): 1659–1668.
Article history
Received:
April 15 2005
Accepted:
November 03 2005
Citation
Clifford C. Taggart, Sally-Ann Cryan, Sinead Weldon, Aileen Gibbons, Catherine M. Greene, Emer Kelly, Teck Boon Low, Shane J. O'Neill, Noel G. McElvaney; Secretory leucoprotease inhibitor binds to NF-κB binding sites in monocytes and inhibits p65 binding . J Exp Med 19 December 2005; 202 (12): 1659–1668. doi: https://doi.org/10.1084/jem.20050768
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