Hypoxia inhibits Moloney murine leukemia virus expression in activated macrophages.
Hypoxia, a local decrease in oxygen tension, occurring in many pathological processes, modifies macrophage (Mphi) gene expression and function. Here, we provide the first evidence that hypoxia inhibits transgene expression driven by the Moloney murine leukemia virus-long terminal repeats (MoMLV-LTR) in IFN-gamma-activated Mphi. Hypoxia silenced the expression of several MoMLV-LTR-driven genes, including v-myc, enhanced green fluorescence protein, and env, and was effective in different mouse Mphi cell lines and on distinct MoMLV backbone-based viruses. Down-regulation of MoMLV mRNA occurred at the transcriptional level and was associated with decreased retrovirus production, as determined by titration experiments, suggesting that hypoxia may control MoMLV retroviral spread through the suppression of LTR activity. In contrast, genes driven by the CMV or the SV40 promoter were up-regulated or unchanged by hypoxia, indicating a selective inhibitory activity on the MoMLV promoter. It is interesting that hypoxia was ineffective in suppressing MoMLV-LTR-controlled gene expression in T or fibroblast cell lines, suggesting a Mphi lineage-selective action. Finally, we found that MoMLV-mediated gene expression in Mphi was also inhibited by picolinic acid, a tryptophan catabolite with hypoxia-like activity and Mphi-activating properties, suggesting a pathophysiological role of this molecule in viral resistance and its possible use as an antiviral agent.
Puppo
Maura
M
Laboratory of Molecular Biology, Istituto Giannina Gaslini, Padiglione 2, L go Gerolamo Gaslini 5, 16147 Genova Quarto, Italy.
Bosco
Maria Carla
MC
Federico
Maurizio
M
Pastorino
Sandra
S
Varesio
Luigi
L
D000818:Animals; D015687:Cell Hypoxia / Q000276:immunology*; D002460:Cell Line; D015967:Gene Expression Regulation, Viral / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D005822:Genetic Vectors / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008979:Moloney murine leukemia virus / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D010848:Picolinic Acids / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020079:Terminal Repeat Sequences / Q000187:drug effects / Q000235:genetics / Q000276:immunology
D010848:Picolinic Acids; D012333:RNA, Messenger; C030614:picolinic acid