INTERLEUKIN-6 ACTIVATES AND REGULATES TRANSCRIPTION FACTORS OF THE INTERFERON REGULATORY FACTOR FAMILY IN M1 CELLS

Activation of (2'-5') A synthetase gene expression in interleukin-6 (I L-6)-treated myeloleukemic M1 cells correlates with protein binding to the interferon response sequence enhancer (IRS). A new interferon res ponse sequence complex, F6, is induced by IL-6 independently of interf eron and is identified here as comprising the interferon regulatory fa ctor-1 (IRF-1) and IRF-2, by use of specific antibodies in DNA mobilit y shift assays with probes containing IRF binding sites. IRF-1 and IRF -2 have, respectively, positive and negative transcriptional effects o n interferon-beta and interferon-inducible genes. In the IL-6-treated M1 or cells, IRF-1 binding is activated early and maximally at 1 h, wh ereas the onset of IRF-2 binding is delayed. In a cell variant M1res, where (2'-5') A synthetase is no more induced, IRF-2 binding is consti tutive, and IRF-1 binding is not seen before or after IL-6 treatment. In sensitive M1or cells, IL-6 rapidly induces IRF-1 mRNA, but in M1res cells, IRF-1 mRNA is constitutively high and not changed by IL-6. IRF -2 mRNA levels are also constitutive and not inducible by IL-6 even in M1or cells. The dissociation between induction of mRNAs and of protei n binding observed suggests that the activity of the IRF proteins is r egulated by IL-6. Transcripts of a third member of the IRF gene family , ICSBP, encoding a protein known to act as repressor, were found to b e strongly down-regulated by IL-6. The rapid activation of IRF-1 and t he modulation of the other transcription factors of this family may pl ay a role in the early phase of IL-6 action on the M1 cells.