Freed B M, Lempert N, Lawrence D A
Department of Surgery, Albany Medical College, New York 12208.
Toxicol Appl Pharmacol. 1991 Jan;107(1):173-82. doi: 10.1016/0041-008x(91)90341-b.
The immunosuppressive properties of polar and nonpolar maleimides were studied by measuring their ability to inhibit mitogen-induced interleukin-2 (IL-2) production by JURKAT T cells. The nonpolar maleimides N-ethylmaleimide (NEM) and N-phenylmaleimide (NPM) inhibited IL-2 production by 85-99%, but only when added to JURKAT cells prior to the mitogen. The polar maleimides N-hydroxymaleimide (NHM) and 4-maleimidosalicylic acid (M84) did not suppress IL-2 production significantly, even though NHM reacted with more cellular thiols (12%) than did NPM (8%). Both NEM and NPM suppressed IL-2 production at doses that did not affect proliferation. NEM inhibited IL-2 production induced by PHA, anti-CD3 (alpha CD3) monoclonal antibodies or PMA, and A23187, but did not interfere with the binding of alpha CD3 to the cells. NEM inhibited IL-2 production at concentrations that did not interfere with the PHA-induced increase in intracellular free calcium [( Ca]i). Neither NPM nor NHM inhibited the rise in [Ca]i, even at the highest concentrations tested. Although JURKAT T cells require both PMA and A23187 to induce IL-2 production, we found that cells pretreated with PMA could respond to A23187 added 18 hr later. PMA-treated cells were not resistant to the immunosuppressive effects of NEM or NPM. However, PMA-pretreated cells became resistant to the inhibitory effects of NEM upon the addition of A23187, suggesting that nonpolar maleimides inhibit activation events induced by the rise in [Ca]i.
通过测量极性和非极性马来酰亚胺抑制有丝分裂原诱导的JURKAT T细胞产生白细胞介素-2（IL-2）的能力，研究了它们的免疫抑制特性。非极性马来酰亚胺N-乙基马来酰亚胺（NEM）和N-苯基马来酰亚胺（NPM）抑制IL-2产生的程度达85%-99%，但前提是在有丝分裂原之前添加到JURKAT细胞中。极性马来酰亚胺N-羟基马来酰亚胺（NHM）和4-马来酰亚胺基水杨酸（M84）并未显著抑制IL-2产生，尽管NHM与更多的细胞硫醇反应（12%），而NPM为（8%）。NEM和NPM均在不影响增殖的剂量下抑制IL-2产生。NEM抑制由PHA、抗CD3（αCD3）单克隆抗体或PMA以及A23187诱导的IL-2产生，但不干扰αCD3与细胞的结合。NEM在不干扰PHA诱导的细胞内游离钙[Ca]i升高的浓度下抑制IL-2产生。即使在测试的最高浓度下，NPM和NHM均未抑制[Ca]i的升高。尽管JURKAT T细胞需要PMA和A23187两者来诱导IL-2产生，但我们发现用PMA预处理的细胞能够对18小时后添加的A23187作出反应。经PMA处理的细胞对NEM或NPM的免疫抑制作用不具有抗性。然而，添加A23187后，经PMA预处理的细胞对NEM的抑制作用产生抗性，这表明非极性马来酰亚胺抑制由[Ca]i升高诱导的激活事件。
