RelA/p65 is a molecular target for the immunosuppressive action of protein kinase A

EMBO J. 1995 May 1;14(9):1991-2004. doi: 10.1002/j.1460-2075.1995.tb07191.x.


Stimulation of the protein kinase A (PKA) signalling pathway exerts an inhibitory effect on the proliferation of numerous cells, including T lymphocytes. In CD4+ T helper cells, stimulation of PKA leads to suppression of interleukin 2 (IL-2) induction, while induction of the genes coding for the lymphokines IL-4 and IL-5 is enhanced. We show that the differential effect of PKA activity on induction of the IL-2 and IL-4 genes is mediated through their promoters. One major target of the suppressive effect of PKA is the kappa B site in the IL-2 promoter. A kappa B site is missing in the IL-4 promoter. Mutations preventing factor binding to the IL-2 kappa B site result in a loss of PKA-mediated suppression of IL-2 promoter activity. Furthermore, activation of the PKA signalling pathway impairs the inducible activity of multiple kappa B sites of the IL-2 promoter, but not of other factor binding sites. The reduction in activity of kappa B sites in activated and PKA-stimulated T cells is accompanied by changes in the concentration and DNA binding of Rel/NF-kappa B factors. Stimulation of the PKA pathway in Jurkat T cells with the PKA activator forskolin leads to an increase in synthesis of c-Rel and p105/p50, while synthesis of p65/RelA remains unchanged. However, nuclear translocation and DNA binding of p65 is distinctly impaired, probably due to a retarded degradation of I kappa B-alpha. In a similar way, stimulation of the PKA signalling pathway inhibits nuclear translocation of p65 and generation of nuclear kappa B complexes in peripheral T lymphocytes from murine lymph nodes. These results indicate that PKA-mediated suppression of NF-kappa B activity plays an important role in the control of activation of peripheral T lymphocytes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Cell Nucleus / metabolism
  • Colforsin / pharmacology
  • Cyclic AMP-Dependent Protein Kinases / immunology*
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Enzyme Activation
  • Humans
  • Immune Tolerance / physiology*
  • Interleukin-2 / genetics
  • Interleukin-4 / genetics
  • Lymphocyte Activation
  • Mice
  • NF-kappa B / metabolism*
  • Promoter Regions, Genetic
  • Signal Transduction / drug effects
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Transcription Factor RelA


  • Interleukin-2
  • NF-kappa B
  • Transcription Factor RelA
  • Colforsin
  • Interleukin-4
  • Cyclic AMP-Dependent Protein Kinases