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B and C/EBP-mediated mechanism
* To whom correspondence should be addressed. E-mail: tbigby{at}ucsd.edu.
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 mRNA expression and gene transcription in the human monocyte-like cell line, THP-1. 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 IkBa and p50/p65 proteins. EMSA/supershift and DNase I footprint analyses revealed that p50 binds to an atypical NF-B site located in the proximal FLAP promoter, while chromatin immunoprecipitation assays demonstrated that LPS induced binding of p50, but not 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 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.
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