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This Article Full Text Full Text (PDF) All Versions of this Article: 292/1/L215    most recent 00023.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Serio, K. J. Articles by Mao, J. T. Search for Related Content PubMed PubMed Citation Articles by Serio, K. J. Articles by Mao, J. T.

TNF- downregulates the leukotriene C₄ synthase gene in mononuclear phagocytes

¹Division of Pulmonary and Critical Care Medicine, Department of Medicine, Department of Veterans Affairs San Diego Healthcare System and University of California, San Diego, and ²Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California

Submitted 17 January 2006 ; accepted in final form 12 September 2006

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 h. 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 were 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 LT release and LTC₄ synthase gene expression in monocytes/macrophages via a transcriptional mechanism.

inflammation; lipoxygenase; Toll-like receptor; lipopolysaccharides