RELA/P65 IS A MOLECULAR TARGET FOR THE IMMUNOSUPPRESSIVE ACTION OF PROTEIN-KINASE-A
RELA/P65 IS A MOLECULAR TARGET FOR THE IMMUNOSUPPRESSIVE ACTION OF PROTEIN-KINASE-A
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DOI：
10.1002/j.1460-2075.1995.tb07191.x
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发表时间：
1995-05-01
期刊：
影响因子：
11.4
通讯作者：
SERFLING, E
中科院分区：
文献类型：
--
作者：
NEUMANN, M;GRIESHAMMER, T;SERFLING, E
蛋白激酶A （PKA）信号通路的刺激对包括T淋巴细胞在内的许多细胞的增殖具有抑制作用，在CD4(+) T辅助细胞中，PKA的刺激导致白细胞介素2 （IL-2）的诱导抑制，而编码淋巴因子IL-4和IL-5的基因的诱导增强。我们发现PKA活性对IL-2和IL-4基因诱导的差异作用是通过它们的启动子介导的。PKA抑制作用的一个主要靶点是IL-2启动子中的kappa B位点，在IL-4启动子中缺失kappa B位点，阻止因子结合IL-2 kappa B位点的突变导致PKA介导的IL-2启动子活性抑制丧失，此外，PKA信号通路的激活会损害IL-2启动子中多个kappa B位点的诱导活性，但不会损害其他因子结合位点的诱导活性。活化和PKA刺激的T细胞中kappa B位点活性的降低伴随着Rel/NF-kappa B因子浓度和DNA结合的变化，PKA激活剂forskolin刺激Jurkat T细胞中的PKA通路导致c-Rel和p105/p50的合成增加，而p65/RelA的合成保持不变，然而，p65的核易位和DNA结合明显受损，可能是由于I kappa B- α的降解迟缓。同样，刺激PKA信号通路可抑制小鼠淋巴结外周T淋巴细胞p65的核易位和核kappa B复合物的产生，这些结果表明PKA介导的NF-kappa B活性抑制在控制外周T淋巴细胞的活化中起重要作用。
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.