Activation of the Interleukin-6 promoter by a dominant negative mutant of c-Jun

Biochim Biophys Acta. 2004 May 28;1692(1):17-24. doi: 10.1016/j.bbamcr.2004.03.001.


The human IL-6 promoter contains multiple regulatory elements such as those binding transcription factors belonging to the NF-kappaB (-75/-63), C/EBP (-158/-145 and -87/-76) and AP-1 (-283/-277) families. Herein, we report that ectopic expression of c-Jun, C/EBPdelta, and the p65 subunit of NF-kappaB synergistically activates an IL-6 promoter construct containing only a TATA box and a kappaB binding site. These results suggest that interactions among NF-kappaB, C/EBP, and AP-1, which are all activated by the most powerful physiological inducers of the IL-6 gene, namely TNF-alpha and IL-1, may be crucial for maximal activation of the IL-6 promoter in response to the two cytokines. Furthermore, we show that a mutated form of c-Jun lacking the transactivation domain (TAM-67) was a much stronger activator of the IL-6 promoter than c-Jun. In combination with p65 and/or C/EBPdelta, TAM-67 also synergistically activated the IL-6 promoter, while it inhibited TNF-alpha induced AP-1 activity directing an AP-1-responsive reporter plasmid. Lastly, electrophoretic mobility shift assay (EMSA) results strongly suggest the formation of complexes between p65, C/EBPdelta, and/or c-Jun or TAM-67 on the kappaB site, supporting the idea that the functional synergism is determined by a physical interaction. These data provide new insight into the molecular mechanisms regulating the formation of the transcription complex responsible for IL-6 promoter activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • CCAAT-Enhancer-Binding Protein-delta
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Calcium-Binding Proteins*
  • Genes, Reporter
  • HeLa Cells
  • Humans
  • Interleukin-6 / genetics*
  • Membrane Glycoproteins / metabolism
  • Mutation
  • NF-kappa B / metabolism
  • Nerve Tissue Proteins / metabolism
  • Peptide Fragments / metabolism
  • Plasmids / metabolism
  • Promoter Regions, Genetic*
  • Protein Binding
  • Protein Biosynthesis
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-jun / genetics*
  • Proto-Oncogene Proteins c-jun / metabolism
  • Synaptotagmin I
  • Synaptotagmins
  • Transcription Factor AP-1 / metabolism
  • Transcription Factor RelA
  • Transcription Factors*
  • Transcription, Genetic
  • Transcriptional Activation
  • Transfection


  • CCAAT-Enhancer-Binding Proteins
  • CEBPD protein, human
  • Calcium-Binding Proteins
  • Interleukin-6
  • Membrane Glycoproteins
  • NF-kappa B
  • Nerve Tissue Proteins
  • Peptide Fragments
  • Proto-Oncogene Proteins c-jun
  • Synaptotagmin I
  • TAM67 peptide
  • Transcription Factor AP-1
  • Transcription Factor RelA
  • Transcription Factors
  • Synaptotagmins
  • CCAAT-Enhancer-Binding Protein-delta