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

Macrophage activation determines the outcome of infection by Mycobacterium tuberculosis (Mtb). Interferon-gamma (IFN-gamma) activates macrophages by d riving Janus tyrosine kinase (JAK)/signal transducer and activator of trans cription-dependent induction of transcription and PKR-dependent suppression of translation. Microarray-based experiments reported here enlarge this pi cture. 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 wa s transcriptional. Five times as many genes related to immunity and inflamm ation were induced than suppressed. Mtb mimicked or synergized with IFN-gam ma more than antagonized its actions. Phagocytosis of nonviable Mtb or poly styrene beads affected many genes, but the transcriptional signature of mac rophages infected with viable Mtb was distinct. Studies involving macrophag es deficient in inducible nitric oxide synthase and/or phagocyte oxidase re vealed that these two antimicrobial enzymes help orchestrate the profound t ranscriptional remodeling that underlies macrophage activation.