Interleukin-10 induces inhibitory C/EBPβ 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/EBP beta 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 beta, demonstrating that other cytokines can induce this repressor. LIPS 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/lEBP beta. In contrast, in undifferentiated THP-1 monocytes, IL-10 did not inhibit HIV-1 replication or induce C/EBP beta. IL-10 signal transduction uses STAT-3, and macrophages from STAT-3(-/-) mice fail to produce inhibitory C/EBP beta after LPS or IL-10 stimulation. Transfection of STAT-3 into THP-1 cells enhances C/EBP beta 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 beta. Differentiation induced post-transcriptional regulation is required to produce inhibitory C/EBP beta 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.