Bray R, Abrams S, Brahmi Z
Cell Immunol. 1983 May;78(1):100-13. doi: 10.1016/0008-8749(83)90263-0.
Natural killer (NK) cell-mediated cytotoxicity, as measured by the lysis of the human erythroleukemic cell line K562, is inhibited by the glucocorticosteroid dexamethasone (DEX). Kinetic analysis revealed that DEX inhibits an early event(s) in the lytic mechanism and that the inhibition is both transient and readily reversible if DEX is removed. The inhibition is not due to the production of a DEX-induced inhibitory protein or decreased target-cell binding. Attempts to counter the effects of DEX through the addition of inducers of NK activity were unsuccessful. Neither the calcium ionophore A23187 nor exogenous cyclic GMP was able to reverse the inhibition by DEX. The addition of arachidonic acid (AA), a pharmacologically active metabolite of phospholipase A-2 activation, was also unsuccessful in reversing the effects of DEX. In fact, AA itself inhibited NK activity in a dose-dependent fashion. This inhibition was not due to reduced target binding and was observed even in the presence of indomethacin. It is concluded that DEX blocks an early membrane-signaling event necessary to activate the lytic mechanism and that inhibition was not through some alternative mechanism. Inhibition of NK activity by arachidonic acid is not yet understood but most likely is not a result of enhanced prostaglandin synthesis. Hence, the study of DEX and AA inhibition provides a new approach to unravel some of the intricacies surrounding NK-mediated tumor target destruction.
通过人红白血病细胞系K562的裂解来测定的自然杀伤（NK）细胞介导的细胞毒性受到糖皮质激素地塞米松（DEX）的抑制。动力学分析表明，DEX抑制了裂解机制中的早期事件，并且如果去除DEX，这种抑制是短暂的且易于逆转。这种抑制不是由于产生了DEX诱导的抑制蛋白或靶细胞结合减少。通过添加NK活性诱导剂来对抗DEX作用的尝试未成功。钙离子载体A23187和外源性环鸟苷酸都不能逆转DEX的抑制作用。添加花生四烯酸（AA），一种磷脂酶A - 2激活的药理活性代谢产物，也未能逆转DEX的作用。事实上，AA本身以剂量依赖性方式抑制NK活性。这种抑制不是由于靶细胞结合减少，并且即使在存在吲哚美辛的情况下也能观察到。结论是，DEX阻断了激活裂解机制所必需的早期膜信号事件，并且这种抑制不是通过某种替代机制。花生四烯酸对NK活性的抑制作用尚不清楚，但很可能不是前列腺素合成增强的结果。因此，对DEX和AA抑制作用的研究为揭示围绕NK介导的肿瘤靶细胞破坏的一些复杂性提供了一种新方法。
