The Journal of Experimental Medicine · 2001 · 462 citations · 68 references
Life SciencesImmunologyMolecular BiologyGene ExpressionInflammationInnate ImmunityCytokine BiologyImmune Gene RegulationInflammatory SignalingInnate Immune Signaling PathwaysInterferon ResponsesMacrophage BiologyInterferon Gamma ResponseMacrophage Inflammatory ResponsesMacrophage Responses To BacteriaMacrophage Transcriptional RegulationMicroarray-based TranscriptomicsMycobacterium Tuberculosis InfectionTranscriptional ActivatorsTranscriptional Signature Analysis
Macrophage activation determines the outcome of Mtb infection, and IFN‑γ drives JAK/STAT‑dependent transcriptional induction and PKR‑dependent translational suppression. The study uses microarray experiments to expand understanding of macrophage transcriptional responses. The authors examined macrophages lacking inducible nitric oxide synthase or phagocyte oxidase, showing these enzymes orchestrate the transcriptional remodeling of activation. Exposure to IFN‑γ and/or Mtb altered 25 % of the macrophage genome, with more genes suppressed than induced—most suppression being transcriptional—yet fivefold more immunity‑related genes were induced; Mtb largely mimicked or synergized with IFN‑γ, and viable Mtb produced a distinct transcriptional signature compared to phagocytosis of nonviable bacteria or beads, with inducible nitric oxide synthase and phagocyte oxidase orchestrating this remodeling.
Macrophage activation determines the outcome of infection by Mycobacterium tuberculosis (Mtb). Interferon-γ (IFN-γ) activates macrophages by driving Janus tyrosine kinase (JAK)/signal transducer and activator of transcription–dependent induction of transcription and PKR-dependent suppression of translation. Microarray-based experiments reported here enlarge this picture. Exposure to IFN-γ and/or Mtb led to altered expression of 25% of the monitored genome in macrophages. The number of genes suppressed by IFN-γ exceeded the number of genes induced, and much of the suppression was transcriptional. Five times as many genes related to immunity and inflammation were induced than suppressed. Mtb mimicked or synergized with IFN-γ more than antagonized its actions. Phagocytosis of nonviable Mtb or polystyrene beads affected many genes, but the transcriptional signature of macrophages infected with viable Mtb was distinct. Studies involving macrophages deficient in inducible nitric oxide synthase and/or phagocyte oxidase revealed that these two antimicrobial enzymes help orchestrate the profound transcriptional remodeling that underlies macrophage activation.
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Functional Discovery via a Compendium of Expression Profiles
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Production of large amounts of hydrogen peroxide by human tumor cells.
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