Shi, S., Nathan, C., Schnappinger, D., Drenkow, J., Fuortes, M., Block, E., Ding, A., Gingeras, T. R., Schoolnik, G., Akira, S., Takeda, K., Ehrt, S. (2003) MyD88 primes macrophages for full-scale activation by interferon-γ yet mediates few responses to Mycobacterium tuberculosis. Journal of Experimental Medicine, 198 (7). pp. 987-997. ISSN 00221007 (ISSN)
Abstract
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)-γ from 5- to 100-fold less extensively in MyD88-/- macrophages than in WT macrophages. Thus, widespread, full-scale activation of macrophages by IFN-γ 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 κB, which synergizes with IFN-γ 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-γ-dependent activation, whereas macrophages can respond to a complex microbial stimulus, the tubercle bacillus, chiefly by other routes.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Innate immunity Macrophage activation Microarray gene expression analysis NF-κB Toll-like receptors alpha interferon differentiation inducing factor immunoglobulin enhancer binding protein interleukin 6 myeloid differentiation factor 88 nitric oxide synthase RANTES toll like receptor tumor necrosis factor unclassified drug animal experiment animal model article cell killing controlled study dendritic cell enzyme linked immunosorbent assay flow cytometry gene expression regulation gene induction genetic regulation immune response mouse Mycobacterium tuberculosis nonhuman priority journal reverse transcription polymerase chain reaction signal transduction Adaptor Proteins, Signal Transducing Animals Antigens Differentiation Interferon Type II Interleukin-1 Macrophages Membrane Glycoproteins Mice Mice, Inbred C57BL NF-kappa B Receptors Cell Surface Receptors Immunologic Tumor Necrosis Factor-alpha |
| Subjects: | bioinformatics > genomics and proteomics > analysis and processing > microarray gene expression processing organs, tissues, organelles, cell types and functions > cell types and functions > cell types > macrophages organs, tissues, organelles, cell types and functions > cell types and functions > cell types > macrophages organs, tissues, organelles, cell types and functions > cell types and functions > cell types > macrophages |
| CSHL Authors: | |
| Communities: | CSHL labs > Gingeras lab |
| Depositing User: | CSHL Librarian |
| Date: | 2003 |
| Date Deposited: | 13 Mar 2012 14:15 |
| Last Modified: | 15 Jul 2013 15:45 |
| PMCID: | PMC2194223 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/25290 |
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