Tian L, Lawrence D A
Wadsworth Center, Albany, New York 12201-0509, USA.
Toxicol Appl Pharmacol. 1996 Dec;141(2):540-7. doi: 10.1006/taap.1996.0320.
Macrophages (M phi) can be induced to produce nitric oxide (NO), which has been suggested to be important for macrophages to exercise various functions. We have previously reported that an environmental toxicant, lead (Pb), can significantly inhibit NO production by murine splenic M phis. Herein, eight additional metal ions, gold (Au), cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), mercury (Hg), nickel (Ni), and zinc (Zn), were assessed. In addition to Pb, Hg and Cd significantly suppressed NO production by cytokine (interferon-gamma and tumor necrosis factor-alpha)-stimulated murine M phis. Au and Cu also were inhibitory, but less than Pb, Hg, and Cd. In contrast, Cr and Zn were not modulatory, and Ni and Co significantly enhanced NO production by cytokine-stimulated M phis. The enhancement by Ni and Co was inhibited by the arginine analog N-monomethylarginine. The metals showed different activating/inhibiting profiles when added to a cell-free (activated M phi lysate) NO-producing-system in which inducible NO synthase (iNOS) is already expressed. Cr, Cu, Pb, and Zn moderately suppressed iNOS, which suggests that they may directly modify enzyme or cofactor activity. Cd, Hg, Mg, Ni, or Co did not produce any significant effect on NO production by the cell-free system. Inhibition of NO production by Pb-exposed M phis was not due to decreased expression of iNOS nor limited to its modest direct inhibition of iNOS; thus, other mechanism(s) must be accountable for the efficient Pb-induced inhibition of NO production by M phi. Ni or Co did induce a substantial increase of iNOS protein. Overall, these observations provide additional insight into the means by which metals via inhibition or enhancement of NO production may be pathogenic, by suppression of defense mechanisms or induction of hypersensitivity, respectively.
巨噬细胞（M phi）可被诱导产生一氧化氮（NO），据认为这对巨噬细胞行使各种功能很重要。我们之前报道过，一种环境毒物铅（Pb）可显著抑制小鼠脾脏M phi产生NO。在此，我们评估了另外八种金属离子，金（Au）、镉（Cd）、钴（Co）、铬（Cr）、铜（Cu）、汞（Hg）、镍（Ni）和锌（Zn）。除了Pb，Hg和Cd也显著抑制细胞因子（干扰素-γ和肿瘤坏死因子-α）刺激的小鼠M phi产生NO。Au和Cu也有抑制作用，但比Pb、Hg和Cd弱。相比之下，Cr和Zn没有调节作用，而Ni和Co显著增强细胞因子刺激的M phi产生NO。Ni和Co的增强作用被精氨酸类似物N-单甲基精氨酸抑制。当将这些金属添加到已表达诱导型一氧化氮合酶（iNOS）的无细胞（活化M phi裂解物）NO产生系统中时，它们表现出不同的激活/抑制模式。Cr、Cu、Pb和Zn适度抑制iNOS，这表明它们可能直接改变酶或辅因子的活性。Cd、Hg、Mg、Ni或Co对无细胞系统产生NO没有任何显著影响。Pb暴露的M phi产生NO的抑制并非由于iNOS表达降低，也不限于其对iNOS的适度直接抑制；因此，其他机制必定是Pb有效诱导M phi产生NO受抑制的原因。Ni或Co确实诱导了iNOS蛋白的大量增加。总体而言，这些观察结果为金属通过抑制或增强NO产生分别通过抑制防御机制或诱导超敏反应而致病的方式提供了更多见解。
