Interleukin-6 modulates interferon-regulated gene expression by inducing the ISGF3 gamma gene using CCAAT/enhancer binding protein-beta (C/EBP-beta)

Although interleukin-6 (IL-6) alone does not induce the expression of IFN s timulated genes (ISG), a low dose priming of cells with IL-6 strongly enhan ces the cellular responses to interferon-alpha (IFN-alpha). This effect of IL-6 is not due to superstimulation of the JAK-STAT pathway. Rather, IL-6 i nduces expression of ISGF3 gamma (p48), a subunit of the multimeric transcr iption factor ISGF3. As a result IFN-alpha robustly activates gene transcri ption in IL-6 primed cells. We have shown earlier that the transcription of ISGF3 gamma gene is regulated through a novel element GATE (gamma-IFN acti vated transcriptional element). We show here IL-6 induces the ISGF3 gamma g ene through GATE. Transcription factor C/EBP-beta is required for inducing ISGF3 gamma gene expression through GATE. A mutant C/EBP-beta inhibits the IL-6 inducible ISGF3 gamma gene expression through GATE. Together, these re sults establish a molecular basis for the synergy between IFNs and IL-6. (C ) 2000 Elsevier Science B.V. All rights reserved.