The Journal of Experimental Medicine
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Published 15 October 2001. doi:10.1084/jem.194.8.1123
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© The Rockefeller University Press, 0022-1007/2001/10/1123/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 8, October 15, 2001 1123-1140

Original Article

Reprogramming of the Macrophage Transcriptome in Response to Interferon-{gamma} and Mycobacterium tuberculosis: Signaling Roles of Nitric Oxide Synthase-2 and Phagocyte Oxidase



Sabine Ehrta, Dirk Schnappingerd, Stefan Bekiranovb, Jörg Drenkowe, Shuangping Shia,c, Thomas R. Gingerase, Terry Gaasterlandb, Gary Schoolnikd, and Carl Nathana,c

a Department of Microbiology and Immunology, Weill Medical College of Cornell University, the
b Laboratory of Computational Genomics, The Rockefeller University,
c Immunology Program, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021
d Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305
e Affymetrix, Inc., Santa Clara, CA 95051
Cornell University Weill Medical College, 1300 York Ave., Box 57, New York, NY 10021.212-746-8536212-746-6505

cnathan{at}med.cornell.edu

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.

Key Words: gene expression • microarray analysis • macrophage activation • innate immunity • phagocytosis

Abbreviations used in this paper: ho, homologous to; IGTP, IFN-induced GTPase; Irg, immune responsive gene; JAK, Janus tyrosine kinase; MRP, myeloid related protein; NO, nitric oxide; phox, phagocyte oxidase; prec, precursor; RANTES, regulated in activated normal T cells, expressed and secreted; RNI, reactive nitrogen intermediates; ROI, reactive oxygen intermediates; SLPI, secretory leukocyte protease inhibitor; STAT, signal transducer and activator of transcription; wt, wild-type.

D. Schnappinger and S. Bekiranov contributed equally to this paper.

© 2001 The Rockefeller University Press


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