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Reprogramming of the macrophage transcriptome in response to interferon-gamma and Mycobacterium tuberculosis: signaling roles of nitric oxide synthase-2 and phagocyte oxidase.

TitleReprogramming of the macrophage transcriptome in response to interferon-gamma and Mycobacterium tuberculosis: signaling roles of nitric oxide synthase-2 and phagocyte oxidase.
Publication TypeJournal Article
Year of Publication2001
AuthorsEhrt S, Schnappinger D, Bekiranov S, Drenkow J, Shi S, Gingeras TR, Gaasterland T, Schoolnik G, Nathan C
JournalJ Exp Med
Volume194
Issue8
Pagination1123-40
Date Published2001 Oct 15
ISSN0022-1007
KeywordsAnimals, Gene Expression Regulation, Interferon-gamma, Macrophage Activation, Macrophages, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Mycobacterium tuberculosis, NADPH Oxidase 2, NADPH Oxidases, Nitric Oxide Synthase, Nitric Oxide Synthase Type II, Oligonucleotide Array Sequence Analysis, Phagocytes, Reproducibility of Results, Signal Transduction, Transcription, Genetic
Abstract

Macrophage activation determines the outcome of infection by Mycobacterium tuberculosis (Mtb). Interferon-gamma (IFN-gamma) 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-gamma and/or Mtb led to altered expression of 25% of the monitored genome in macrophages. The number of genes suppressed by IFN-gamma 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-gamma 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.

DOI10.1084/jem.194.8.1123
Alternate JournalJ Exp Med
PubMed ID11602641
PubMed Central IDPMC2193509
Grant ListAI44826 / AI / NIAID NIH HHS / United States
HL61241-02 / HL / NHLBI NIH HHS / United States

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