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.
Eleven primitive neuroectodermal tumor (PNET) biopsies from infants under the age of 3 years were studied for the presence of various differentiation markers for neuroectodermal stem cells. Special emphasis was placed on the expression of cytokeratin proteins. The tumor cells expressed different cytokeratin proteins (CK8, CK13, CK18, CK19, KL1, AE1/AE3, MNF16) in 3 of 11 cases. These cases were furthermore characterized by a strong expression of glial fibrillary acidic protein, S-100 protein and vimentin. Vimentin and cytokeratin proteins were co-expressed; cross-reactivity between these two intermediate filaments could be excluded by immunoblotting. It is noteworthy that the three positive tumors were all from infants in their 1st year. We assume that PNETs in early infancy are characterized by a particularly wide range of differentiation patterns. The presence of cytokeratin proteins in these cases seems to be associated with the expression of vimentin and must be regarded as an indicator of an early developmental stage of the tumor cells.
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