Cyclic adenosine monophosphate-responsive elements are involved in the transcriptional activation of the human IL-10 gene in monocytic cells

Eur J Immunol. 1999 Oct;29(10):3098-104. doi: 10.1002/(SICI)1521-4141(199910)29:10<3098::AID-IMMU3098>3.0.CO;2-H.


IL-10 plays an important role in the regulation of immune responses. We and others have demonstrated recently that cyclic adenosine monophosphate (cAMP)-elevating substances up-regulate monocytic IL-10 expression in vitro and in vivo. Computer analysis of the IL-10 promoter/enhancer region localized four putative cAMP-responsive elements (CRE1- 4) with homology to the CRE consensus motif. In electrophoretic mobility shift assays CRE1 and CRE4 bound protein complexes consisting of transcription factors CREB-1 and ATF-1, while CRE3 bound only marginal amounts of CREB-1/ATF-1 in combination with unknown protein(s). CRE2 showed no protein binding activity. In vitro mutation of CRE1 and CRE4 reduced the level of cAMP-stimulated transactivation in reporter gene assays in comparison to the wild-type promoter by 20 % and 50 %, respectively, while mutation of CRE3 had no effect. The main action of CRE4 on cAMP-dependent stimulation is probably based on its adjacent localization to the TATA box and its sequence comprising a perfect half site. Experiments with double and triple mutants and with deleted promoter fragments indicated the participation of additional elements beside the CRE motifs in the cAMP-dependent stimulation. Our data suggest that intracellular cAMP may directly affect expression of the immunoregulatory cytokine IL-10 in monocytic cells via activation of the eukaryotic transcription factors CREB-1 and ATF-1 and their binding to CRE1 and CRE4 in the upstream enhancer of the IL-10 promoter.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cyclic AMP / genetics*
  • Cyclic AMP / immunology
  • Humans
  • Interleukin-10 / genetics*
  • Interleukin-10 / immunology
  • Leukemia, Monocytic, Acute
  • Monocytes / immunology
  • Monocytes / metabolism*
  • Promoter Regions, Genetic / genetics
  • Promoter Regions, Genetic / immunology
  • Response Elements / immunology*
  • Transcriptional Activation / immunology*
  • Tumor Cells, Cultured


  • Interleukin-10
  • Cyclic AMP