Prostaglandin E2 impairs CD4+ T cell activation by inhibition of Ick.: Implications in Hodgkin's lymphoma
Prostaglandin E2 impairs CD4+ T cell activation by inhibition of Ick.: Implications in Hodgkin's lymphoma
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DOI：
10.1158/0008-5472.can-05-3252
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发表时间：
2006-01-15
期刊：
影响因子：
11.2
通讯作者：
Schultze, JL
中科院分区：
文献类型：
--
作者：
Chemnitz, JM;Driesen, J;Schultze, JL
包括霍奇金淋巴瘤在内的许多肿瘤都与细胞免疫力下降和前列腺素E-2（PGE（2））水平升高有关，前列腺素E-2是一种已知的CD 4（+）T细胞活化抑制剂，被认为与癌症的免疫偏离有关。为了阐明肿瘤源性PGE（2）对原代人CD 4（+）T细胞的分子机制，我们使用了基于全基因组的转录方法，并显示PGE（2）严重限制了通过T细胞受体和CD 28信号传导诱导的基因表达变化。这些数据表明，PGE（2）在T细胞受体信号传导的早期阶段存在干扰：事实上，PGE（2）刺激T细胞导致1ck失活和ZAP 70磷酸化减少。抗凋亡基因逃避PGE（2）诱导的抑制，导致部分保护细胞凋亡，对辐射或Fas介导的信号。作为一种功能性结果，PGE（2）处理的CD 4（+）T细胞在细胞周期中被阻滞，这与细胞周期蛋白/细胞周期蛋白依赖性激酶抑制剂p27（kip 1）的上调有关。最重要的是，霍奇金淋巴瘤中的CD 4（+）T细胞显示出类似的基因调控，这些基因在体外被健康个体的T细胞中的PGE 2改变。这些数据有力地表明，PGE 2是导致霍奇金淋巴瘤中观察到的CD 4（+）T细胞损伤的重要因素。
Many tumors, including Hodgkin's lymphoma, are associated with decreased cellular immunity and elevated levels of prostaglandin E-2 (PGE(2)), a known inhibitor of CD4(+) T cell activation, suggested to be involved in immune deviation in cancer. To address the molecular mechanisms tumor-derived PGE(2) might have on primary human CD4(+) Tcells, we used a whole genome-based transcriptional approach and show that PGE(2) severely limited changes of gene expression induced by signaling through the T cell receptor and CD28. This data suggests an interference of PGE(2) at an early step of T cell receptor signaling: indeed, PGE(2) stimulation of T cells leads to inactivation of 1ck and reduced phosphorylation of ZAP70. Antiapoptotic genes escaped PGE(2)-induced inhibition resulting in partial protection from apoptosis in response to irradiation or Fas-mediated signaling. As a functional consequence, PGE(2)-treated CD4(+) T cells are arrested in the cell cycle associated with up-regulation of the cyclin/cyclin-dependent kinase inhibitor p27(kip1). Most importantly, CD4(+) T cells in Hodgkin's lymphoma show similar regulation of genes that were altered in vitro by PGE2 in T cells from healthy individuals. These data strongly suggest that PGE2 is an important factor leading to CD4(+) T cell impairment observed in Hodgkin's lymphoma.