Lipopolysaccharide down-regulates the leukotriene C4 synthase gene in the monocyte-like cell line, THP-1.
We studied the effects of LPS on cysteinyl leukotriene (LT) synthesis and LTC(4) 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 LTC(4) release. The putative LPS receptor, Toll-like receptor 4, was expressed in THP-1 cells. LPS down-regulated LTC(4) 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 LTC(4) synthase mRNA decay. LPS treatment of THP-1 cells, transiently transfected with a LTC(4) synthase promoter (1.35 kb)-reporter construct, decreased promoter activity. Neutralization of TNF-alpha 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-kappaB activation resulted in inhibition of the LPS effect, while activation of NF-kappaB and p50/p65 overexpression down-regulated the LTC(4) synthase gene. LPS down-regulates cysteinyl LT release and LTC(4) synthase gene expression in mononuclear phagocytes by an NF-kappaB-mediated mechanism.
Serio
Kenneth J
KJ
Department of Medicine, Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA.
Johns
Scott C
SC
Luo
Linda
L
Hodulik
Craig R
CR
Bigby
Timothy D
TD
D019138:Antibodies, Blocking / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002460:Cell Line; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000276:immunology*; D029721:Drosophila Proteins; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D017997:Leukotriene C4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009000:Monocytes / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D052002:NF-kappa B p50 Subunit; D011401:Promoter Regions, Genetic / Q000276:immunology; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects / Q000276:immunology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013997:Time Factors; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D051996:Transcription Factor RelA; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology; D017968:Vanadium Compounds / Q000494:pharmacology
D019138:Antibodies, Blocking; D029721:Drosophila Proteins; D007106:Immune Sera; D007476:Ionophores; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D017968:Vanadium Compounds; C472777:bisperoxovanadium; D017997:Leukotriene C4; D000001:Calcimycin; D005982:Glutathione Transferase; D020928:Mitogen-Activated Protein Kinases; C041116:leukotriene-C4 synthase