RelA/p65 is a molecular target for the immunosuppressive action of protein kinase A.
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.
Neumann
M
M
Institute of Pathology, University of Würzburg, Germany.
Grieshammer
T
T
Chuvpilo
S
S
Kneitz
B
B
Lohoff
M
M
Schimpl
A
A
Franza
B R
BR
Serfling
E
E
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000276:immunology* / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D007108:Immune Tolerance / Q000502:physiology*; D007376:Interleukin-2 / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics; D008213:Lymphocyte Activation; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051996:Transcription Factor RelA
D007376:Interleukin-2; D016328:NF-kappa B; D051996:Transcription Factor RelA; D005576:Colforsin; D015847:Interleukin-4; D017868:Cyclic AMP-Dependent Protein Kinases