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CELLULAR METABOLISM

Lipopolysaccharide induces 5-lipoxygenase-activating protein gene expression in THP-1 cells via a NF-B and C/EBP-mediated mechanism

Department of Medicine, Department of Veterans Affairs San Diego Healthcare System, and the University of California, San Diego, San Diego, California

Submitted 23 June 2004 ; accepted in final form 21 December 2004

We examined induced expression of the 5-lipoxygenase-activating protein (FLAP), which is critical for leukotriene synthesis in mononuclear phagocytes. Prolonged exposure to the bacterial component, lipopolysaccharide (LPS), increased FLAP gene transcription, mRNA expression, and protein expression in the human monocyte-like THP-1 cell line. Activation and inhibition of the NF-B pathway modulated LPS induction of FLAP gene expression. An NF-B-mediated mechanism of action was supported by overexpression of dominant-negative IB and p50/p65 proteins. EMSA/supershift and DNase I footprint analyses revealed that p50 binds to an NF-B site located in the proximal FLAP promoter, while chromatin immunoprecipitation assays demonstrated that LPS induced binding of p50 but not of p65. Moreover, EMSA/supershift analyses demonstrated that LPS induced time-dependent binding of THP-1 nuclear extracts (containing p50) to this promoter region. Mutation of the NF-B site decreased basal promoter activity and abolished the p50- and p65-associated induction. EMSA/supershift analyses also demonstrated that LPS induced binding of THP-1 nuclear extracts [containing CCAAT/enhancer binding protein (C/EBP)-, -, and -] to a C/EBP site located adjacent to the NF-B site in the FLAP promoter. We conclude that LPS enhances FLAP gene expression via both NF-B- and C/EBP-mediated transcriptional mechanisms in mononuclear phagocytes.

monocytes/macrophages; endotoxin shock; inflammation; allergy

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