TNF-alpha downregulates the leukotriene C4 synthase gene in mononuclear phagocytes.
We studied the effect of tumor necrosis factor (TNF)-alpha exposure on cysteinyl leukotriene (LT) synthesis by cells of monocyte/macrophage lineage. TNF-alpha conditioning of monocytic THP-1 cells and primary human monocytes resulted in a decreased capacity for LTC(4) release. TNF-alpha exposure (for 16-24 h) decreased LTC(4) synthase mRNA in THP-1 cells, primary mouse bone marrow-derived macrophages, and eosinophilic AML14.3D10 cells. TNF-alpha downregulated LTC(4) synthase mRNA in THP-1 cells in a dose- and time-dependent manner, with downregulation observed as early as 4 h. The effect of TNF-alpha on LTC(4) synthase mRNA expression was mediated via the MEK/ERK pathway, but not via cyclooxygenase or nitric oxide synthase pathways. Conditioning of actinomycin D-treated cells with TNF-alpha did not accelerate degradation of LTC(4) synthase mRNA. TNF-alpha produced sustained activation of p50 and p65, which were previously reported by our group to decrease LTC(4) synthase promoter activity. In transiently transfected THP-1 cells, TNF-alpha decreased promoter activity via an element located within the first 620 bp of the promoter. We conclude that TNF-alpha exposure downregulates the synthetic capacity for cysteinyl LT release and LTC(4) synthase gene expression in monocytes/macrophages via a transcriptional mechanism.
Serio
Kenneth J
KJ
Division of Pulmonary and Critical Care Medicine, Department of Medicine, VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. kjserio@ucsd.edu
Luo
Colin
C
Luo
Linda
L
Mao
Jenny T
JT
D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D007476:Ionophores / Q000494:pharmacology; D017997:Leukotriene C4 / Q000096:biosynthesis; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010586:Phagocytes / Q000187:drug effects* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D007476:Ionophores; D016328:NF-kappa B; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D017997:Leukotriene C4; D000001:Calcimycin; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase