Youn J, Borghesi L A, Olson E A, Lynes M A
Department of Molecular and Cell Biology, University of Connecticut, Storrs 06269-3125, USA.
J Toxicol Environ Health. 1995 Aug;45(4):397-413. doi: 10.1080/15287399509532004.
Metallothionein (MT) is a thiol-rich protein that is rapidly induced by exposure to heavy metal cations. We have previously demonstrated that exogenous MT stimulates murine splenocytes to proliferate, but inhibits humoral responses to antigen. These observations suggest that metallothionein released from cells has a complex role in heavy metal-mediated immune dysfunction. Here we examine one possible mechanism by which MT mediates suppression of humoral immunity. Exposure of macrophages to 20 microM MT did not affect their ability to engulf opsonized sheep erythrocytes, but in the presence of 20 microM MT, peritoneal macrophages were stimulated to produce increased levels of oxygen radicals. These results correlated with observations that while macrophage phagocytosis of opsonized Candida albicans was unaltered by the presence of exogenous MT, killing of the engulfed yeast cells was dramatically enhanced by 20 microM MT. Amounts of free cadmium and zinc equimolar to that added as Zn,Cd-MT had no effect on candidacidal activity. MT was also found to significantly decrease lymphocyte proliferation mediated by macrophage activity. Biotinylated MT (MT-b) bound specifically to the plasma membranes of these macrophages, suggesting that membrane-associated molecules of the macrophage may transduce a signal mediated by MT binding. These results demonstrate that macrophages are a sensitive target for MT-mediated immunomodulation and that some of the consequences of the MT interaction with macrophages may be alterations in the capacity to produce an effective immune response and increased extracellular exposure to damaging free radicals.
金属硫蛋白（MT）是一种富含硫醇的蛋白质，暴露于重金属阳离子时会迅速被诱导产生。我们之前已经证明，外源性MT能刺激小鼠脾细胞增殖，但会抑制对抗原的体液免疫反应。这些观察结果表明，细胞释放的金属硫蛋白在重金属介导的免疫功能障碍中具有复杂的作用。在此，我们研究MT介导体液免疫抑制的一种可能机制。将巨噬细胞暴露于20微摩尔的MT中并不影响其吞噬调理过的绵羊红细胞的能力，但在存在20微摩尔MT的情况下，腹腔巨噬细胞被刺激产生更高水平的氧自由基。这些结果与以下观察结果相关，即虽然外源性MT的存在并未改变巨噬细胞对调理过的白色念珠菌的吞噬作用，但20微摩尔的MT显著增强了对被吞噬酵母细胞的杀伤作用。与作为锌镉金属硫蛋白添加的等摩尔游离镉和锌的量对杀念珠菌活性没有影响。还发现MT能显著降低由巨噬细胞活性介导的淋巴细胞增殖。生物素化的MT（MT-b）特异性结合这些巨噬细胞的质膜，表明巨噬细胞的膜相关分子可能转导由MT结合介导的信号。这些结果表明，巨噬细胞是MT介导的免疫调节的敏感靶点，并且MT与巨噬细胞相互作用的一些后果可能是产生有效免疫反应的能力改变以及细胞外暴露于有害自由基增加。
