IL-1β-specific up-regulation of neutrophil gelatinase-associated lipocalin is controlled by IκB-ζ

Jack B. Cowland, Tatsushi Muta, Niels Borregaard

Research output: Contribution to journalArticlepeer-review

115 Citations (Scopus)

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-1β, but not by TNF-α, despite an induction of NF-κB binding to the NGAL promoter by both cytokines. In this study, we present evidence that the IL-1β specificity is caused by a requirement of the NGAL promoter for the NF-κB-binding cofactor IκB-ζ for transcriptional activation. Up-regulation of NGAL expression in A549 cells following IL-1β stimulation was dependent on de novo protein synthesis and was greatly diminished by a small interfering against IκB-ζ mRNA. Cotransfection of A549 cells with a plasmid expressing IκB-ζmade TNF-α capable of inducing NGAL transcription, indicating that IκB-ζ induction is the only factor discriminating between IL-1β and TNF-α in their ability to induce NGAL expression. Coexpression of the cofactor Bcl-3, which is closely related to IκB-ζ, did not enable TNF-α to induce NGAL transcription. A functional NF-κB site of the NGAL promoter was required for IκB-ζ to exert its effect. The human β defensin 2 gene also required IκB-ζ for its IL-1β-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.

Original languageEnglish
Pages (from-to)5559-5566
Number of pages8
JournalJournal of Immunology
Volume176
Issue number9
DOIs
Publication statusPublished - 2006 May 1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'IL-1β-specific up-regulation of neutrophil gelatinase-associated lipocalin is controlled by IκB-ζ'. Together they form a unique fingerprint.

Cite this