Am. J. Respir. Cell Mol. Biol., Volume 25, Number 1, July, 2001 84-91

Cytokine-Mediated Induction of the Human Elafin Gene in Pulmonary Epithelial Cells Is Regulated by Nuclear Factor-B

Lynne Bingle, Teresa D. Tetley, and Colin D. Bingle

Respiratory Cell and Molecular Biology Laboratory, Division of Genomic Medicine, University of Sheffield Medical School, Sheffield; and Respiratory Medicine, National Heart & Lung Institute, Charing Cross Hospital, Imperial College School of Medicine, London, United Kingdom

Elafin, a low molecular-weight proteinase inhibitor, is a member of the recently described trappin gene family. These proteins are thought to play important roles in the regulation of inflammation and are expressed in multiple epithelia. Elafin is found within the lung, and its expression can be induced by inflammatory mediators. The molecular mechanisms that mediate its induction are not understood. In this study we investigated the transcriptional regulation of the elafin gene in pulmonary epithelial cell lines. Transfection of elafin promoter constructs into the elafin-expressing pulmonary epithelial cell line A549 identified a number of positive-acting elements. Cytokine-mediated inducibility of the elafin gene promoter was shown to occur through a nuclear factor (NF)-B site present within the minimal promoter. This site was shown to bind to NF-B proteins within nuclear extracts from cytokine stimulated cell lines as well as to in vitro-translated RelA. Cotransfection with both RelA and NF-B-inducing kinase induced reporter gene activation via this site, and mutagenesis experiments confirmed that it was crucial for induction of elafin gene activity. These results clearly identify a role for elafin in the inflammatory response of the airway epithelium to pathogenic insult and show that this response is mediated by an NF-B site within the proximal promoter.

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