title: Hypoxia selectively inhibits monocyte chemoattractant protein-1 production by macrophages.
abstract: Hypoxia, a local decrease in oxygen tension occurring in inflammatory and tumor lesions, modulates gene expression in macrophages. Because macrophages are important chemokine producers, we investigated the regulatory effects of hypoxia on macrophage-derived chemokines. We demonstrated that hypoxia inhibits the production of the macrophage and T lymphocyte chemotactic and activating factor, monocyte chemoattractant protein-1 (MCP-1). Exposure of mouse macrophages to low oxygen tension resulted in the down-regulation of constitutive MCP-1 mRNA expression and protein secretion. Hypoxia inhibitory effects were selective for MCP-1 because the chemokines macrophage inflammatory protein-1beta (MIP-1beta), RANTES, IFN-gamma-inducible protein-10, and MIP-2 were not affected, and MIP-1alpha was induced. Hypoxia also inhibited, in a time-dependent fashion, MCP-1 up-regulation by IFN-gamma and LPS. Moreover, the inhibitory action of hypoxia was exerted on human monocytic cells. MCP-1 down-regulation was associated with inhibition of gene transcription and mRNA destabilization, suggesting a dual molecular mechanism of control. Finally, we found that the triptophan catabolite picolinic acid and the iron chelator desferrioxamine, which mimic hypoxia in the induction of gene expression, differentially regulated the expression of MCP-1. This study characterizes a novel property of hypoxia as a selective inhibitor of MCP-1 production induced by different stimuli in macrophages and demonstrates that down-regulation of gene expression by hypoxia can be controlled at both transcriptional and posttranscriptional levels. Inhibition of MCP-1 may represent a negative regulatory mechanism to control macrophage-mediated leukocyte recruitment in pathological tissues.
authors.affiliation: Laboratory of Molecular Biology, G. Gaslini Institute, Genova, Italy. mcbosco1@virgilio.it
authors.forename: Maria Carla
authors.initials: MC
authors.lastname: Bosco
authors.forename: Maura
authors.initials: M
authors.lastname: Puppo
authors.forename: Sandra
authors.initials: S
authors.lastname: Pastorino
authors.forename: Zenghui
authors.initials: Z
authors.lastname: Mi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Melillo
authors.forename: Stefano
authors.initials: S
authors.lastname: Massazza
authors.forename: Annamaria
authors.initials: A
authors.lastname: Rapisarda
authors.forename: Luigi
authors.initials: L
authors.lastname: Varesio
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D003676:Deferoxamine / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000378:metabolism; D010848:Picolinic Acids / Q000494:pharmacology; D020871:RNA Stability / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology
chemical_list: D018932:Chemokine CCL2; D008070:Lipopolysaccharides; D010848:Picolinic Acids; D012333:RNA, Messenger; D007371:Interferon-gamma; D003676:Deferoxamine; C030614:picolinic acid; D010100:Oxygen