Differentiation of monocytes to macrophages switches the Mycobacterium tuberculosis effect on HIV-1 replication from stimulation to inhibition: modulation of interferon response and CCAAT/enhancer binding protein beta expression.
HIV-1 replication is inhibited in uninflamed lung macrophages and is stimulated during tuberculosis. Attempts to recapitulate activation of HIV-1 replication in primary monocytes and macrophages ex vivo and in the untreated and PMA-treated THP-1 cell line model in vitro have produced opposite results depending on the state of differentiation of the cells. After infection with Mycobacterium tuberculosis, monocytes enhanced HIV-1 replication and produced a stimulatory 37-kDa CCAAT/enhancer binding protein beta (C/EBPbeta) transcription factor, whereas macrophages suppressed HIV-1 replication and produced an inhibitory 16-kDa C/EBPbeta transcription factor. IFN-beta induced inhibitory 16-kDa C/EBPbeta in macrophages, but had no effect on C/EBPbeta expression in monocytes. Macrophages, but not monocytes, were able to activate IFN-stimulated gene factor-3 (ISGF-3), a transcription factor composed of STAT-1, STAT-2, and IFN regulatory factor (IRF)-9, after infection with M. tuberculosis or stimulation with type I IFN. Macrophages expressed IRF-9 DNA-binding activity, but monocytes did not, and addition of the IRF-9 component reconstituted ISGF-3 in extracts of IFN-treated monocytes. Modulation of IFN responsiveness upon differentiation occurred at least in part through a post-transcriptionally regulated increase in IRF-9 expression. Both monocytes and macrophages maintained IFN responsiveness, activating STAT-1 homodimer formation and transcription of the STAT-1 gene after IFN stimulation. In addition, both monocytes and macrophages were able to activate NF-kappaB upon infection with M. tuberculosis. These results show that induction of ISGF-3, expression of the inhibitory 16-kDa C/EBPbeta, and suppression of HIV-1 replication via a transcriptional mechanism are macrophage-specific responses to infection with M. tuberculosis.
Division of Pulmonary and Critical Care Medicine and Bellevue Chest Service, Department of Pathology, New York University Medical Center, New York, NY 10016, USA.
M
M
Weiden
N
N
Tanaka
Y
Y
Qiao
B Y
BY
Zhao
Y
Y
Honda
K
K
Nakata
A
A
Canova
D E
DE
Levy
W N
WN
Rom
R
R
Pine
D022762:CCAAT-Enhancer-Binding Proteins; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D007249:Inflammation / Q000276:immunology; D007370:Interferon Type I / Q000378:metabolism; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016899:Interferon-beta / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000821:virology; D008970:Molecular Weight; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000821:virology; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000378:metabolism; D020033:Protein Isoforms / Q000096:biosynthesis; D011499:Protein Processing, Post-Translational / Q000276:immunology; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000276:immunology; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology; D014779:Virus Replication / Q000276:immunology*
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; C494227:IRF9 protein, human; D007370:Interferon Type I; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009687:Nuclear Proteins; D020033:Protein Isoforms; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016899:Interferon-beta