TNF-alpha downregulates the leukotriene C4 synthase gene in mononuclear phagocytes.
Am J Physiol Lung Cell Mol Physiol
; 292(1): L215-22, 2007 Jan.
Article
em En
| MEDLINE
| ID: mdl-16980379
ABSTRACT
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fagócitos
/
Fator de Necrose Tumoral alfa
/
Glutationa Transferase
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article