The Journal of Experimental Medicine
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Published online 29 September 2003 doi:10.1084/jem.20030603
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© Rockefeller University Press, 0022-1007/2003/10/987 $5.00
The Journal of Experimental Medicine, Volume 198, Number 7, 987-997

MyD88 Primes Macrophages for Full-Scale Activation by Interferon-{gamma} yet Mediates Few Responses to Mycobacterium tuberculosis

Shuangping Shi1, Carl Nathan1,2, Dirk Schnappinger2, Jörg Drenkow4, Michele Fuortes3, Ellen Block1, Aihao Ding2, Thomas R. Gingeras4, Gary Schoolnik5, Shizuo Akira6, Kiyoshi Takeda6 and Sabine Ehrt2

1 Graduate Program in Immunology, Weill Graduate School of Medical Sciences
2 Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021
3 Department of Surgery, Weill Medical College of Cornell University, New York, NY 10021
4 Affymetrix, Inc., Santa Clara, CA 95051
5 Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305
6 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 565-0871 Osaka, Japan

Address correspondence to Sabine Ehrt, Weill Medical College of Cornell University, Box 62, 1300 York Avenue, New York, NY 10021. Phone: (212) 746-2994; Fax: (212) 746-8536; email: sae2004{at}med.cornell.edu

Macrophages are activated from a resting state by a combination of cytokines and microbial products. Microbes are often sensed through Toll-like receptors signaling through MyD88. We used large-scale microarrays in multiple replicate experiments followed by stringent statistical analysis to compare gene expression in wild-type (WT) and MyD88-/- macrophages. We confirmed key results by quantitative reverse transcription polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay. Surprisingly, many genes, such as inducible nitric oxide synthase, IRG-1, IP-10, MIG, RANTES, and interleukin 6 were induced by interferon (IFN)-{gamma} from 5- to 100-fold less extensively in MyD88-/- macrophages than in WT macrophages. Thus, widespread, full-scale activation of macrophages by IFN-{gamma} requires MyD88. Analysis of the mechanism revealed that MyD88 mediates a process of self-priming by which resting macrophages produce a low level of tumor necrosis factor. This and other factors lead to basal activation of nuclear factor {kappa}B, which synergizes with IFN-{gamma} for gene induction. In contrast, infection by live, virulent Mycobacterium tuberculosis (Mtb) activated macrophages largely through MyD88-independent pathways, and macrophages did not need MyD88 to kill Mtb in vitro. Thus, MyD88 plays a dynamic role in resting macrophages that supports IFN-{gamma}–dependent activation, whereas macrophages can respond to a complex microbial stimulus, the tubercle bacillus, chiefly by other routes.

Key Words: macrophage activation • Toll-like receptors • innate immunity • NF-{kappa}B • microarray gene expression analysis


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