scholarly journals Reprogramming of the Macrophage Transcriptome in Response to Interferon-γ and Mycobacterium tuberculosis

2001 ◽  
Vol 194 (8) ◽  
pp. 1123-1140 ◽  
Author(s):  
Sabine Ehrt ◽  
Dirk Schnappinger ◽  
Stefan Bekiranov ◽  
Jörg Drenkow ◽  
Shuangping Shi ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Macrophage Activation ◽  
Interferon Γ ◽  
Altered Expression ◽  
Transcriptional Signature ◽  
Number Of Genes ◽  
Phagocyte Oxidase ◽  
Ifn Γ ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

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

scholarly journals Murine Macrophages Secrete Interferon γ upon Combined Stimulation with Interleukin (IL)-12 and IL-18: A Novel Pathway of Autocrine Macrophage Activation

1998 ◽  
Vol 187 (12) ◽  
pp. 2103-2108 ◽  
Author(s):  
Markus Munder ◽  
Moisés Mallo ◽  
Klaus Eichmann ◽  
Manuel Modolell
Keyword(s):  
Macrophage Activation ◽  
Interferon Γ ◽  
Biologically Active ◽  
Efficient Production ◽  
Activated T Cells ◽  
Murine Bone Marrow ◽  
Ifn Γ ◽  
Low Levels ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

Interferon (IFN)-γ, a key immunoregulatory cytokine, has been thought to be produced solely by activated T cells and natural killer cells. In this study, we show that murine bone marrow– derived macrophages (BMMΦ) secrete large amounts of IFN-γ upon appropriate stimulation. Although interleukin (IL)-12 and IL-18 alone induce low levels of IFN-γ mRNA transcripts, the combined stimulation of BMMΦ with both cytokines leads to the efficient production of IFN-γ protein. The macrophage-derived IFN-γ is biologically active as shown by induction of inducible nitric oxide synthase as well as upregulation of CD40 in macrophages. Our findings uncover a novel pathway of autocrine macrophage activation by demonstrating that the macrophage is not only a key cell type responding to IFN-γ but also a potent IFN-γ–producing cell.

scholarly journals MyD88 Primes Macrophages for Full-Scale Activation by Interferon-γ yet Mediates Few Responses to Mycobacterium tuberculosis

2003 ◽  
Vol 198 (7) ◽  
pp. 987-997 ◽  
Author(s):  
Shuangping Shi ◽  
Carl Nathan ◽  
Dirk Schnappinger ◽  
Jörg Drenkow ◽  
Michele Fuortes ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Large Scale ◽  
Nuclear Factor Κb ◽  
Interferon Γ ◽  
Full Scale ◽  
Enzyme Linked Immunosorbent Assay ◽  
Ifn Γ ◽  
Microbial Products ◽  
Oxide Synthase

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.

scholarly journals Widespread Bronchogenic Dissemination Makes DBA/2 Mice More Susceptible than C57BL/6 Mice to Experimental Aerosol Infection with Mycobacterium tuberculosis

2003 ◽  
Vol 71 (10) ◽  
pp. 5845-5854 ◽  
Author(s):  
Pere-Joan Cardona ◽  
Sergi Gordillo ◽  
Jorge Díaz ◽  
Gustavo Tapia ◽  
Isabel Amat ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Reference Strain ◽  
Lavage Fluid ◽  
Mrna Levels ◽  
Pulmonary Infiltration ◽  
Ifn Γ ◽  
Aerosol Infection ◽  
Oxide Synthase ◽  
Foamy Macrophages ◽  
Inducible Nitric Oxide

ABSTRACT We have used the murine model of aerosol-induced experimental tuberculosis to assess the effects of four clinical isolates and a reference strain of Mycobacterium tuberculosis on resistant C57BL/6 mice and susceptible DBA/2 mice. Histological studies and detection of 25 cytokines potentially involved in the infection were carried out. DBA/2 mice showed higher concentrations of bacilli in bronchoalveolar lavage fluid and lung tissue. Furthermore, these mice evidenced a larger granulomatous infiltration in the parenchyma due to an increased rate of emigration of infected foamy macrophages from the granulomas to the neighboring pulmonary alveolar spaces. The better control of bacillary concentrations and pulmonary infiltration observed in C57BL/6 mice from week 3 postinfection could result from their higher RANTES, ICAM-1, and gamma interferon (IFN-γ) mRNA levels. On the other hand, the higher MIP-2 and MCP-3 mRNA levels seen in DBA/2 mice would result in stronger lung recruitment of macrophages and neutrophils. Additionally, DBA/2 mice showed increased inducible nitric oxide synthase expression, induced by the larger number of foamy macrophages, at weeks 18 and 22. This increment was a consequence of phagocytosed bacillary debris, was independent of IFN-γ expression, and could exert only a bacteriostatic effect. The results of the study suggest that DBA/2 mice are more susceptible than C57BL/6 mice to M. tuberculosis infection due to a higher bronchial dissemination of bacilli inside poorly activated foamy macrophages.

scholarly journals Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis.

1996 ◽  
Vol 183 (5) ◽  
pp. 2293-2302 ◽  
Author(s):  
S Nicholson ◽  
M da G Bonecini-Almeida ◽  
J R Lapa e Silva ◽  
C Nathan ◽  
Q W Xie ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mycobacterium Tuberculosis ◽  
Nitric Oxide Synthase ◽  
Bronchoalveolar Lavage ◽  
Inducible Nitric Oxide Synthase ◽  
Alveolar Macrophages ◽  
Mononuclear Phagocytes ◽  
Mycobacterium Tuberculosis Infection ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

The high-output pathway of nitric oxide production helps protect mice from infection by several pathogens, including Mycobacterium tuberculosis. However, based on studies of cells cultured from blood, it is controversial whether human mononuclear phagocytes can express the corresponding inducible nitric oxide synthase (iNOS;NOS2). The present study examined alveolar macrophages fixed directly after bronchopulmonary lavage. An average of 65% of the macrophages from 11 of 11 patients with untreated, culture-positive pulmonary tuberculosis reacted with an antibody documented herein to be monospecific for human NOS2. In contrast, a mean of 10% of bronchoalveolar lavage cells were positive from each of five clinically normal subjects. Tuberculosis patients' macrophages displayed diaphorase activity in the same proportion that they stained for NOS2, under assay conditions wherein the diaphorase reaction was strictly dependent on NOS2 expression. Bronchoalveolar lavage specimens also contained NOS2 mRNA. Thus, macrophages in the lungs of people with clinically active Mycobacterium tuberculosis infection often express catalytically competent NOS2.

scholarly journals Expression of the Nitric Oxide Synthase 2 Gene Is Not Essential for Early Control of Mycobacterium tuberculosis in the Murine Lung

2000 ◽  
Vol 68 (12) ◽  
pp. 6879-6882 ◽  
Author(s):  
Andrea M. Cooper ◽  
John E. Pearl ◽  
Jason V. Brooks ◽  
Stefan Ehlers ◽  
Ian M. Orme
Keyword(s):  
Nitric Oxide ◽  
Mycobacterium Tuberculosis ◽  
Nitric Oxide Synthase ◽  
Low Dose ◽  
Interleukin 12 ◽  
Infection Model ◽  
Rapid Progression ◽  
Ifn Γ ◽  
Nitric Oxide Synthase 2 ◽  
Oxide Synthase

ABSTRACT The interleukin-12 and gamma interferon (IFN-γ) pathway of macrophage activation plays a pivotal role in controlling tuberculosis. In the murine model, the generation of supplementary nitric oxide by the induction of the nitric oxide synthase 2 (NOS2) gene product is considered the principal antimicrobial mechanism of IFN-γ-activated macrophages. Using a low-dose aerosol-mediated infection model in the mouse, we have investigated the role of nitric oxide in controllingMycobacterium tuberculosis in the lung. In contrast to the consequences of a systemic infection, a low dose of bacteria introduced directly into the lungs of mice lacking the NOS2 gene is controlled almost as well as in intact animals. This is in contrast to the rapid progression of disease in mice lacking IFN-γ or a key member of the IFN signaling pathway, interferon regulatory factor 1. Thus while IFN-γ is pivotal in early control of bacterial growth in the lung, this control does not completely depend upon the expression of the NOS2 gene. The absence of inducible nitric oxide in the lung does, however, result in increased polymorphonuclear cell involvement and eventual necrosis in the pulmonary granulomas of the infected mice lacking the NOS2 gene.

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