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  • Title: IL-1beta-specific up-regulation of neutrophil gelatinase-associated lipocalin is controlled by IkappaB-zeta.
    Author: Cowland JB, Muta T, Borregaard N.
    Journal: J Immunol; 2006 May 01; 176(9):5559-66. PubMed ID: 16622025.
    Abstract:
    Neutrophil gelatinase-associated lipocalin (NGAL) is a siderophore-binding protein that exerts a bacteriostatic effect by sequestering iron. Strong induction of NGAL synthesis has been observed in inflamed epithelium of the lungs and colon. Expression of NGAL is up-regulated in the lung epithelial cell line A549 by IL-1beta, but not by TNF-alpha, despite an induction of NF-kappaB binding to the NGAL promoter by both cytokines. In this study, we present evidence that the IL-1beta specificity is caused by a requirement of the NGAL promoter for the NF-kappaB-binding cofactor IkappaB-zeta for transcriptional activation. Up-regulation of NGAL expression in A549 cells following IL-1beta stimulation was dependent on de novo protein synthesis and was greatly diminished by a small interfering against IkappaB-zeta mRNA. Cotransfection of A549 cells with a plasmid expressing IkappaB-zeta made TNF-alpha capable of inducing NGAL transcription, indicating that IkappaB-zeta induction is the only factor discriminating between IL-1beta and TNF-alpha in their ability to induce NGAL expression. Coexpression of the cofactor Bcl-3, which is closely related to IkappaB-zeta, did not enable TNF-alpha to induce NGAL transcription. A functional NF-kappaB site of the NGAL promoter was required for IkappaB-zeta to exert its effect. The human beta defensin 2 gene also required IkappaB-zeta for its IL-1beta-specific induction in A549 cells. Our findings indicate that a common regulatory mechanism has evolved to control expression of a subset of antimicrobial proteins expressed in epithelial cells.
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