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Lipopolysaccharide Down-Regulates the Leukotriene C₄ Synthase Gene in the Monocyte-Like Cell Line, THP-1 ¹

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

We studied the effects of LPS on cysteinyl leukotriene (LT) synthesis and LTC₄ synthase expression in mononuclear phagocytes. Conditioning of the monocyte-like cell line, THP-1, with LPS for 7 days resulted in significantly decreased ionophore-stimulated LTC₄ release. The putative LPS receptor, Toll-like receptor 4, was expressed in THP-1 cells. LPS down-regulated LTC₄ synthase mRNA in THP-1 cells in a dose- and time-dependent manner, with down-regulation observed as early as 4 h. Conditioning of actinomycin D-treated cells with LPS resulted in no change in the rate of LTC₄ synthase mRNA decay. LPS treatment of THP-1 cells, transiently transfected with a LTC₄ synthase promoter (1.35 kb)-reporter construct, decreased promoter activity. Neutralization of TNF- and inhibition of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase did not inhibit the effect of LPS. Treatment of cells with a Toll-like receptor 4-blocking Ab and an inhibitor of NF-B activation resulted in inhibition of the LPS effect, while activation of NF-B and p50/p65 overexpression down-regulated the LTC₄ synthase gene. LPS down-regulates cysteinyl LT release and LTC₄ synthase gene expression in mononuclear phagocytes by an NF-B-mediated mechanism.

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