Chronic lymphocytic leukemia and B and T cells differ in their response to cyclic nucleotide phosphodiesterase inhibitors.
Chronic lymphocytic leukemia and B and T cells differ in their response to cyclic nucleotide phosphodiesterase inhibitors.
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DOI：
10.4049/jimmunol.0804255
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发表时间：
2009-05-01
期刊：
影响因子：
--
通讯作者：
Lerner A
中科院分区：
文献类型：
--
作者：
Meyers JA;Su DW;Lerner A
PDE4抑制剂通过减少cAMP分解代谢激活cAMP信号，已知可诱导B系慢性淋巴细胞白血病（CLL）细胞凋亡，但不诱导正常的人T细胞凋亡。对这种敏感性差异的解释仍然未知。在这里，我们报告了对比CLL细胞和正常人类T细胞和B细胞对PDE4抑制剂治疗反应的研究。在使用PDE4抑制剂罗利普兰治疗后，Affymetrix基因芯片对三种细胞群进行分析，发现CLL样本中一组转录本上调，具有异常高的折叠变化，其中一些可能是代偿性负反馈回路的一部分。高折叠变化是由于CLL细胞的基础转录水平较低，这表明camp介导的信号可能在这种细胞类型中受到异常严格的调节。在两种B系细胞类型中，罗利普兰治疗增加cAMP水平并诱导ATF-1/CREB丝氨酸63/133磷酸化，但在T细胞中没有。作为广谱PDE抑制剂IBMX诱导T细胞CREB磷酸化的治疗，我们测试了一系列家族特异性PDE抑制剂模拟IBMX诱导的ATF-1/CREB磷酸化的能力。虽然单独使用PDE3抑制剂没有作用，但PDE3和PDE4抑制剂联合使用可诱导T细胞中ATF-1/CREB Ser 63/133磷酸化。与这一观察结果一致，PDE3B转录物和蛋白水平在CLL细胞中较低，但在T细胞中很容易检测到。联合抑制PDE3/4不会诱导T细胞凋亡，这表明camp介导的信号转导导致ATF-1/CREB Ser 63/133的强烈磷酸化，不足以诱导T细胞凋亡。
PDE4 inhibitors, which activate cAMP signaling by reducing cAMP catabolism, are known to induce apoptosis in B lineage chronic lymphocytic leukemia (CLL) cells but not normal human T cells. The explanation for such differential sensitivity remains unknown. Here, we report studies contrasting the response to PDE4 inhibitor treatment in CLL cells and normal human T and B cells. Affymetrix gene chip analysis in the three cell populations following treatment with the PDE4 inhibitor rolipram identified a set of up-regulated transcripts with unusually high fold-changes in the CLL samples, several of which are likely part of compensatory negative feedback loops. The high fold-change were due to low basal transcript levels in CLL cells, suggesting that cAMP-mediated signaling may be unusually tightly regulated in this cell type. Rolipram treatment augmented cAMP levels and induced ATF-1/CREB serine 63/133 phosphorylation in both B lineage cell types but not T cells. As treatment with the broad-spectrum PDE inhibitor IBMX induced T cell CREB phosphorylation, we tested a series of family-specific PDE inhibitors for their ability to mimic IBMX-induced ATF-1/CREB phosphorylation. While PDE3 inhibitors alone had no effect, the combination of PDE3 and PDE4 inhibitors induced ATF-1/CREB Ser 63/133 phosphorylation in T cells. Consistent with this observation, PDE3B transcript and protein levels were low in CLL cells but easily detectable in T cells. Combined PDE3/4 inhibition did not induce T cell apoptosis, suggesting that cAMP-mediated signal transduction that leads to robust ATF-1/CREB Ser 63/133 phosphorylation is not sufficient to induce apoptosis in this lymphoid lineage.
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影响因子：
4.1
作者：
EPSTEIN, PM;MORASKI, S;HACHISU, R
通讯作者：
HACHISU, R
DOI：
10.1073/pnas.93.20.11236
发表时间：
1996-10-01
影响因子：
11.1
作者：
Jiang, X;Li, JP;Epstein, PM
通讯作者：
Epstein, PM
影响因子：
56.9
作者：
Li, LS;Yee, C;Beavo, JA
通讯作者：
Beavo, JA
影响因子：
9.2
作者：
Balsalobre, A;Marcacci, L;Schibler, U
通讯作者：
Schibler, U
影响因子：
5.8
作者：
Baldi, P;Long, AD
通讯作者：
Long, AD