Prostaglandin D2, its metabolite 15-d-PGJ2, and peroxisome proliferator activated receptor-γ agonists induce apoptosis in transformed, but not normal, human T lineage cells
Prostaglandin D2, its metabolite 15-d-PGJ2, and peroxisome proliferator activated receptor-γ agonists induce apoptosis in transformed, but not normal, human T lineage cells
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DOI：
10.1046/j.0019-2805.2001.01340.x
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发表时间：
2002-01-01
期刊：
影响因子：
6.4
通讯作者：
Phipps, RP
中科院分区：
文献类型：
--
作者：
Harris, SG;Phipps, RP
前列腺素D-2（PGD（2））由肥大细胞、血小板和肺泡巨噬细胞大量产生，并被认为是一种关键的免疫调节脂质介质。15-脱氧-δ（12，14）-PGJ（2）（15-d-PGJ（2））是PGD（2）的关键代谢物，作为潜在的抗炎介质正在进行深入研究。关于PGD（2）或15-d-PGJ（2）在调节人类T细胞系活性中的作用（如果有的话）知之甚少。在这份报告中，我们证明PGD（2）和15-d-PGJ（2）都具有有效的抗增殖作用，实际上通过凋亡机制杀死恶性细胞来源的人T淋巴细胞系。有趣的是，正常的人类T细胞没有受到类似的影响。尽管T淋巴细胞系表达PGD（2）受体（DP-R）的mRNA，但有效的DP受体激动剂BW 245 C并不抑制细胞的增殖或活力，这表明了另一种作用机制。PGD（2）和15-d-PGJ（2）可以与过氧化物酶体增殖物激活受体γ（PPAR-gamma）结合，该受体与脂质代谢和细胞凋亡有关。暴露于合成的PPAR-gamma配体（例如环格列酮、曲格列酮）模拟了PGD（2）和15-d-PGJ（2）的抑制反应，并诱导转化T细胞的凋亡，这与PPAR-gamma依赖性机制一致。这些观察结果表明，PPAR-gamma配体（可能包括PGD（2））向转化的T淋巴细胞提供强凋亡信号，但不向正常T淋巴细胞提供。因此，需要进一步评估利用PPAR-gamma及其配体作为人T细胞癌治疗剂的功效。
Prostaglandin D-2 (PGD(2)) is abundantly produced by mast cells, platelets, and alveolar macrophages and has been proposed as a key immunoregulatory lipid mediator. 15-Deoxy-Delta(12,14)-PGJ(2) (15-d-PGJ(2)), a key PGD(2) metabolite, is under intense study as a potential anti-inflammatory mediator. Little is known about PGD(2) or the role of 15-d-PGJ(2), if any, in regulating the activities of human T lineage cells. In this report we demonstrate that both PGD(2) and 15-d-PGJ(2) have potent antiproliferative effects, and in fact kill human T lymphocyte lines derived from malignant cells by an apoptotic mechanism. Interestingly, normal human T cells were not similarly affected. Although the T lymphocyte lines express mRNA for the PGD(2) receptor (DP-R), a potent DP receptor agonist, BW245C, did not inhibit the proliferation or viability of the cells, suggesting an alternative mechanism of action. PGD(2) and 15-d-PGJ(2) can bind to the peroxisome proliferator activated receptor-gamma (PPAR-gamma) which is implicated in lipid metabolism and apoptosis. Exposure to synthetic PPAR-gamma ligands (e.g. ciglitazone, troglitazone) mimicked the inhibitory responses of PGD(2) and 15-d-PGJ(2), and induced apoptosis in the transformed T cells consistent with a PPAR-gamma-dependent mechanism. These observations suggest that PPAR-gamma ligands (which may include PGD(2)) provide strong apoptotic signals to transformed, but not normal T lymphocytes. Thus, the efficacy of utilizing PPAR-gamma and its ligands as therapeutics for human T cell cancers needs to be further evaluated.