TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION INDUCED BY VIRUSES AND BY LIPOPOLYSACCHARIDES IN MACROPHAGES - SIMILARITIES AND DIFFERENCES

Tumor necrosis factor (TNF)-alpha gene expression can be induced prima rily in cells of the monocyte-macrophage lineage by a variety of induc ers, including lipopolysaccharides (LPS), phorbol esters, ultraviolet (UV) light, and viruses. In this paper, we analyzed the regulatory mec hanisms of TNF-alpha production induced by infection with the Sendai v irus in RAW 264.7 macrophages. We show that in these cells TNF-alpha s ynthesis results mainly from TNF-alpha mRNA translational activation. Using CAT reporter genes, we identified the UA-rich (UAR) sequences lo calized in the TNF-alpha mRNA 3' untranslated region (UTR) as the main sequence involved in this regulation. This sequence has been previous ly shown to be the essential regulatory element involved in LPS-induce d translational activation of TNF mRNA. Activation of TNF gene express ion by viral infection presents other similarities with those induced by LPS. First, TNF production in response to viral infection is inhibi ted by the protein-tyrosine kinase inhibitor herbimycin A as it is in response to LPS. More specifically, we show here that TNF mRNA transla tional activation induced by viral infection or by LPS is inhibited by pretreating the cells with herbimycin A. Second, TNF production in re sponse to viruses is tissue-specific and is abrogated in RAW 264.7 X N IH3T3 hybrid cells, which lack the ability to produce TNF in response to LPS, as a consequence of a defect in the LPS signaling pathway. How ever, viral infection induces TNF production in LPS-unresponsive C3H/H eJ mouse-derived peritoneal macrophages indicating that viruses and LP S signaling pathways differ for at least one intermediate which is the product of the Lps gene. Finally, we show that this regulatory mechan ism can be triggered by different classes of viruses. (C) 1996 Wiley-L iss, Inc.