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-Specific Up-Regulation of Neutrophil Gelatinase-Associated Lipocalin Is Controlled by I
B-
1
* Department of Hematology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; and
Department of Molecular and Cellular Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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-1
, but not by TNF-
, despite an induction of NF-
B binding to the NGAL promoter by both cytokines. In this study, we present evidence that the IL-1 specificity is caused by a requirement of the NGAL promoter for the NF-B-binding cofactor IB-
for transcriptional activation. Up-regulation of NGAL expression in A549 cells following IL-1 stimulation was dependent on de novo protein synthesis and was greatly diminished by a small interfering against IB- mRNA. Cotransfection of A549 cells with a plasmid expressing IB- made TNF- capable of inducing NGAL transcription, indicating that IB- induction is the only factor discriminating between IL-1 and TNF- in their ability to induce NGAL expression. Coexpression of the cofactor Bcl-3, which is closely related to IB-, did not enable TNF- to induce NGAL transcription. A functional NF-B site of the NGAL promoter was required for IB- to exert its effect. The human defensin 2 gene also required IB- for its IL-1-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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