Submitted on April 15, 2005
Revised on July 13, 2005
IL-10 Induces Inhibitory C/EBP
through STAT-3 and Represses HIV-1 Transcription in Macrophages
Naohiko Tanaka1, Yoshihiko Hoshino1, Jeffrey Gold1, Satomi Hoshino1, Frank Martiniuk1, Takeshi Kurata2, Richard Pine3, David Levy4, William N Rom1, and Michael Weiden1*
1 Division of Pulmonary and Critical Care Medicine, N.Y.U. School of Medicine, New York, NY, USA,
2 National Institutes of Infectious Diseases, Tokyo, Japan,
3 Public Health Research Institute, Newark, NJ, USA,
4 Department of Pathology, N.Y.U. School of Medicine, New York, NY, USA
* To whom correspondence should be addressed. 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 interferon 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 M. tuberculosis derived LAM induce the anti-inflammatory cytokine 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 utilizes 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.
