Interleukin-10 induces inhibitory C/EBPbeta through STAT-3 and represses HIV-1 transcription in macrophages.
Pulmonary tuberculosis (TB) has been characterized by inflammation with increased pro- or anti-inflammatory cytokines produced by macrophages. We have reported that IFN produces inhibitory C/EBPbeta and represses transcription of the HIV-1 LTR in macrophages. STAT-1 and type I IFN receptor knockout mice have macrophages that are defective in IFN signaling, yet LPS stimulation induces inhibitory C/EBPbeta, demonstrating that other cytokines can induce this repressor. LPS or Mycobacterium tuberculosis-derived lipoarabinomannan induce the anti-inflammatory cytokine interleukin (IL)-10, which represses the HIV-1 LTR in differentiated THP-1 macrophages by inducing inhibitory C/EBPbeta. In contrast, in undifferentiated THP-1 monocytes, IL-10 did not inhibit HIV-1 replication or induce C/EBPbeta. IL-10 signal transduction uses STAT-3, and macrophages from STAT-3-/- mice fail to produce inhibitory C/EBPbeta after LPS or IL-10 stimulation. Transfection of STAT-3 into THP-1 cells enhances C/EBPbeta promoter activity. THP-1 differentiation also increases STAT-3 protein, but not STAT-3 gene transcription, and induces a translational regulator, CUG-binding protein, that was essential for production of C/EBPbeta. Differentiation induced post-transcriptional regulation is required to produce inhibitory C/EBPbeta in response to IL-10. Only macrophages are able to repress HIV-1 LTR promoter activity and inhibit viral replication in response to IL-10 or type I IFN.
Tanaka
Naohiko
N
Division of Pulmonary & Critical Care Medicine, Department of Medicine, N.Y.U. School of Medicine, New York, NY 10016, USA.
Hoshino
Yoshihiko
Y
Gold
Jeffrey
J
Hoshino
Satomi
S
Martiniuk
Frank
F
Kurata
Takeshi
T
Pine
Richard
R
Levy
David
D
Rom
William N
WN
Weiden
Michael
M
D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007372:Interferons / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000502:physiology* / Q000821:virology*; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000502:physiology; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D022782:CCAAT-Enhancer-Binding Protein-beta; D004268:DNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D016753:Interleukin-10; D007372:Interferons