Submitted on January 17, 2006
Accepted on September 12, 2006
TNF
DOWNREGULATES THE LEUKOTRIENE C4 SYNTHASE GENE IN MONONUCLEAR PHAGOCYTES
Kenneth J Serio1*, Colin Luo1, Linda Luo1, and Jenny T Mao2
1 Medicine, VA San Diego Healthcare System, San Diego, California, United States; Medicine, UCSD, San Diego, California, United States
2 Medicine, UCLA, Los Angeles, United States
* To whom correspondence should be addressed. E-mail: kjsmdx{at}san.rr.com.
We studied the effect of tumor necrosis factor 
(TNF) exposure on cysteinyl leukotriene (LT) synthesis by cells of monocyte/macrophage lineage. TNF conditioning of monocytic THP-1 cells and primary human monocytes resulted in a decreased capacity for LTC4 release. TNF exposure (for 16-24 h) decreased LTC4 synthase mRNA in THP-1 cells, primary mouse bone marrow-derived macrophages, and eosinophilic AML14.3D10 cells. TNF downregulated LTC4 synthase mRNA in THP-1 cells in a dose- and time-dependent manner, with downregulation observed as early as 4 hrs. The effect of TNF on LTC4 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 did not accelerate degradation of LTC4 synthase mRNA. TNF produced sustained activation of p50 and p65, which have been previously reported by our group to decrease LTC4 synthase promoter activity. In transiently transfected THP-1 cells, TNF decreased promoter activity via an element located within the first 620 bp of the promoter. We conclude that TNF exposure downregulates the synthetic capacity for cysteinyl leukotriene release and LTC4 synthase gene expression in monocytes/macrophages via a transcriptional mechanism.
