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J Inflamm. 1995-1996;46(1):1-12.

Tumor necrosis factor-alpha production induced by viruses and by lipopolysaccharides in macrophages: similarities and differences.

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Department of Molecular Biology, University of Brussels, Rhode Saint Genese, Belgium.


Tumor necrosis factor (TNF)-a gene expression can be induced primarily in cells of the monocyte-macrophage lineage by a variety of inducers, including lipopolysaccharides (LPS), phorbol esters, ultraviolet (UV) light, and viruses. In this paper, we analyzed the regulatory mechanisms of TNF-alpha production induced by infection with the Sendai" virus in RAW 264.7 macrophages. We show that in these cells TNF-a synthesis results mainly from TNF-alpha mRNA translational activation. Using CAT reporter genes, we identified the UA- rich (UAR) sequences localized in the TNF-alpha mRNA 3' untranslated region (UTR) as the main sequence involved in this regulation. This sequence has been previously shown to be the essential regulatory element involved in LPS- induced translational activation of TNF mRNA. Activation of TNF gene expression by viral infection presents other similarities with those induced by LPS. First, TNF production in response to viral infection is inhibited by the protein-tyrosine kinase inhibitor herbimycin A as it is in response to LPS. More specifically, we show here that TNF mRNA translational activation induced by viral infection or by LPS is inhibited by pretreating the cells with herbimycin A. Second, TNF production in response to viruses is tissue-specific and is abrogated in RAW 264.7x NIH3T3 hybrid cells, which lack the ability to produce TNF in response to LPS, as a consequence of a defect in the LPS signaling pathway. However, viral infection induces TNF production in LPS- unresponsive C3H/HeJ mouse-derived peritoneal macro phages indicating that viruses and LPS signaling pathways differ for at least one intermediate which is the product of the Lps gene. Finally, we show that this regulatory mechanism can be triggered by different classes of viruses.

[Indexed for MEDLINE]

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