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 (IL-6)-treated myeloleukemic M1 cells correlates with protein binding to the interferon response sequence enhancer (IRS). A new interferon response sequence complex, F6, is induced by IL-6 independently of interferon and is identified here as comprising the interferon regulatory factor-1 (IRF-1) and IRF-2, by use of specific antibodies in DNA mobility shift assays with probes containing IRF binding sites. IRF-1 and IRF-2 have, respectively, positive and negative transcriptional effects on interferon-beta and interferon-inducible genes. In the IL-6-treated M1or cells, IRF-1 binding is activated early and maximally at 1 h, whereas 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 constitutive, 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 protein binding observed suggests that the activity of the IRF proteins is regulated 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 be strongly down-regulated by IL-6. The rapid activation of IRF-1 and the modulation of the other transcription factors of this family may play a role in the early phase of IL-6 action on the M1 cells.
Harroch
S
S
Department of Molecular Genetics and Virology, Weizmann Institute of Science, Rehovot, Israel.
Gothelf
Y
Y
Watanabe
N
N
Revel
M
M
Chebath
J
J
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D015152:Blotting, Northern; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D004247:DNA; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D006801:Humans; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D015850:Interleukin-6 / Q000502:physiology*; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; C494229:IRF2 protein, human; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D015850:Interleukin-6; C494258:Irf1 protein, mouse; C494230:Irf2 protein, mouse; D010750:Phosphoproteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D004247:DNA