TNF- alpha downregulates the leukotriene C sub(4) 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 sub(4) release. TNF- alpha exposure (for 16-24 h) decreased LTC sub(4) synthase mRNA in THP-1 cells, primary mouse bone marrow-derived macrophages, and eosinophilic AML14.3D10 cells. TNF- alpha downregulated LTC sub(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 sub(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 sub(4) synthase mRNA. TNF- alpha produced sustained activation of p50 and p65, which were previously reported by our group to decrease LTC sub(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 sub(4) synthase gene expression in monocytes/macrophages via a transcriptional mechanism.