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Interleukin-10 Induces Inhibitory C/EBP through STAT-3 and Represses HIV-1 Transcription in Macrophages

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Department of Pathology, and Department of Pediatrics, New York University School of Medicine, New York, New York; Public Health Research Institute, Newark, New Jersey; and National Institutes of Infectious Diseases, Tokyo, Japan

Correspondence and requests for reprints should be addressed to Michael Weiden, Division of Pulmonary & Critical Care Medicine, Department of Medicine, N.Y.U. School of Medicine, 550 First Ave, New York, NY 10016. E-mail: weidem01{at}gcrc.med.nyu.edu

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/EBP 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/EBP, 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/EBP. In contrast, in undifferentiated THP-1 monocytes, IL-10 did not inhibit HIV-1 replication or induce C/EBP. IL-10 signal transduction uses STAT-3, and macrophages from STAT-3^–/– mice fail to produce inhibitory C/EBP after LPS or IL-10 stimulation. Transfection of STAT-3 into THP-1 cells enhances C/EBP 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/EBP. Differentiation induced post-transcriptional regulation is required to produce inhibitory C/EBP 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.

Key Words: infection • innate immunity • repression • transcription factors

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