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J. Biol. Chem., Vol. 280, Issue 43, 36510-36517, October 28, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/43/36510    most recent M507977200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lora, J. M. Articles by Fraser, C. C. Search for Related Content PubMed PubMed Citation Articles by Lora, J. M. Articles by Fraser, C. C. Social Bookmarking                      What's this?

Tumor Necrosis Factor- Triggers Mucus Production in Airway Epithelium through an IB Kinase -dependent Mechanism^*

José M. Lora, Dong Mei Zhang, Sha Mei Liao, Timothy Burwell, Anne Marie King, Philip A. Barker, Latika Singh, Marie Keaveney, Jay Morgenstern, José Carlos Gutiérrez-Ramos, Anthony J. Coyle, and Christopher C. Fraser1

From the Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139 and the Centre for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada

Excessive mucus production by airway epithelium is a major characteristic of a number of respiratory diseases, including asthma, chronic bronchitis, and cystic fibrosis. However, the signal transduction pathways leading to mucus production are poorly understood. Here we examined the potential role of IB kinase (IKK) in mucus synthesis in vitro and in vivo. Tumor necrosis factor- (TNF-) or transforming growth factor- stimulation of human epithelial cells resulted in mucus secretion as measured by MUC5AC mRNA and protein. TNF- stimulation induced IKK-dependent p65 nuclear translocation, mucus synthesis, and production of cytokines from epithelial cells. TNF-, but not transforming growth factor-, induced mucus production dependent on IKK-mediated NF-B activation. In vivo, TNF- induced NF-B as determined by whole mouse body bioluminescence. This activation was localized to the epithelium as revealed by LacZ staining in NF-B-LacZ transgenic mice. TNF--induced mucus production in vivo could also be inhibited by administration into the epithelium of an IKK dominant negative adenovirus. Taken together, our results demonstrated the important role of IKK in TNF--mediated mucus production in airway epithelium in vitro and in vivo.

Received for publication, July 21, 2005

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Millennium Pharmaceuticals, Inc., 35 Landsdowne St., Cambridge, MA 02139. Tel.: 617-670-7498; Fax: 617-444-1498; E-mail: chris.fraser{at}mpi.com.

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