de Bittencourt Júnior P I, Senna S M, Vidor A C, Miyasaka C K, Curi R, Williams J F
Department of Physiology, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
Biochem Mol Biol Int. 1998 Sep;45(6):1243-54.
A severe complication in late-stage cancer patients is host immunosuppression. It is suggested that overproduction of the highly cytostatic and cytotoxic antiproliferative cyclopentenone prostaglandins (CP-PGs) within the plasma of cancer-bearing subjects may contribute to immunosuppression. Lymphoid tissues of Walker 256 tumor-bearing rats accumulate large amounts of CP-PGs while the tumor tissue itself does not. Moreover, tumor cells may present differential sensitivity to CP-PGs due to the expression of the multidrug resistance-associated protein (MRP1) gene product which shows a Mg(2+)-dependent vanadate-sensitive glutathione S-conjugate export ATPase (GS-X pump) activity that extrudes CP-PGs from cells as glutathione S-conjugates. In this study, the possibility that deficient GS-X pump activity in immune cells that may be involved in the accumulation of CP-PGs is investigated. Rat lymph node lymphocytes do not exhibit any notable activity even when mitogen-stimulated. Conversely, although rat peritoneal resident (quiescent) or thioglycollate-stimulated (inflammatory) macrophages exhibit low GS-X pump activity, Bacillus Calmette-Guérin (BCG)-activated macrophages show a notable rise in the activity of the ATPase, suggesting that the cellular activation state may modulate GS-X pump activity/expression and that, under appropriate stimuli (e.g., during immune response) macrophages may provide a self-defense against electrophilic CP-PGs by forming GS-conjugates that can be extruded from cells through the GS-X pump. ras oncogene expression may be linked with MRP1/GS-X pump expression/activity, since C2C12 promyoblasts transformed by v-H-ras transfection doubled GS-X pump activity. These results support the proposition that the accumulation of CP-PGs and the immunosuppression of tumor-bearing subjects may be attributed to a lack of GS-X pump activity/expression in lymphocytes.
晚期癌症患者的一种严重并发症是宿主免疫抑制。有研究表明，荷瘤受试者血浆中具有高度细胞抑制和细胞毒性的抗增殖环戊烯酮前列腺素（CP-PGs）过量产生可能导致免疫抑制。携带Walker 256肿瘤的大鼠的淋巴组织中积累了大量的CP-PGs，而肿瘤组织本身却没有。此外，由于多药耐药相关蛋白（MRP1）基因产物的表达，肿瘤细胞对CP-PGs可能表现出不同的敏感性，该基因产物具有一种Mg(2+)依赖性钒酸盐敏感的谷胱甘肽S-共轭物输出ATP酶（GS-X泵）活性，可将CP-PGs作为谷胱甘肽S-共轭物从细胞中排出。在本研究中，对可能参与CP-PGs积累的免疫细胞中GS-X泵活性不足的可能性进行了研究。大鼠淋巴结淋巴细胞即使在有丝分裂原刺激下也不表现出任何显著活性。相反，尽管大鼠腹腔驻留（静止）或巯基乙酸盐刺激（炎症）的巨噬细胞表现出低GS-X泵活性，但卡介苗（BCG）激活的巨噬细胞的ATP酶活性显著升高，这表明细胞激活状态可能调节GS-X泵活性/表达，并且在适当的刺激下（例如在免疫反应期间），巨噬细胞可能通过形成可通过GS-X泵从细胞中排出的GS-共轭物来提供对亲电子CP-PGs的自我防御。ras癌基因表达可能与MRP1/GS-X泵表达/活性相关，因为经v-H-ras转染转化的C2C12成肌细胞前体细胞的GS-X泵活性增加了一倍。这些结果支持了这样一种观点，即CP-PGs的积累和荷瘤受试者的免疫抑制可能归因于淋巴细胞中GS-X泵活性/表达的缺乏。
