Cytokine-mediated induction of the human elafin gene in pulmonary epithelial cells is regulated by nuclear factor-kappa B

Elafin, a low molecular-weight proteinase inhibitor, is a member of the rec ently described trappin gene family. These proteins are thought to play imp ortant roles in the regulation of inflammation and are expressed in multipl e epithelia. Elafin is found within the lung, and its expression tan be ind uced by inflammatory mediators. The molecular mechanisms that mediate its i nduction are not understood. In this study we investigated the transcriptio nal regulation of the elafin gene in pulmonary epithelial cell lines. Trans fection of elafln 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 occ ur through a nuclear factor (NF)-kappaB site present within the minimal pro moter. This site was shown to bind to NF-KB proteins within nuclear extract s from cytokine stimulated cell lines as well as to in vitro-translated Rel A. Cotransfection with both RelA and NF-kappaB-inducing kinase induced repo rter gene activation via this site, and mutagenesis experiments confirmed t hat it was crucial for induction of elafin gene activity. These results cle arly 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-kappaB site within the proximal promoter.