TNF-α downregulates the leukotriene C 4 synthase gene in mononuclear phagocytes

We studied the effect of tumor necrosis factor (TNF)-α exposure on cysteinyl leukotriene (LT) synthesis by cells of monocyte/macrophage lineage. TNF-α conditioning of monocytic THP-1 cells and primary human monocytes resulted in a decreased capacity for LTC 4 release. TNF-α 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-α 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-α 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-α did not accelerate degradation of LTC 4 synthase mRNA. TNF-α 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-α decreased promoter activity via an element located within the first 620 bp of the promoter. We conclude that TNF-α exposure downregulates the synthetic capacity for cysteinyl LT release and LTC 4 synthase gene expression in monocytes/macrophages via a transcriptional mechanism.