Secretion of toxic oxygen products by macrophages: regulatory cytokines and their effects on the oxidase.
Secretion of toxic oxygen products by macrophages: regulatory cytokines and their effects on the oxidase.
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巨噬细胞分泌有毒氧产物：调节细胞因子及其对氧化酶的影响。
DOI：
10.1002/9780470720998.ch14
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发表时间：
1986
期刊：
影响因子：
--
通讯作者：
Tsunawaki,S
中科院分区：
文献类型：
--
作者：
Nathan,CF;Tsunawaki,S
摘要。我们正在尝试鉴定调节巨噬细胞分泌活性氧中间体（ROI）的细胞因子，并分析其作用的生化基础。在人类和小鼠中，干扰素 y (IFN-y) 似乎是由克隆未选择的淋巴细胞分泌的主要因子，可增强巨噬细胞氧化代谢和抗原虫活性。体内给予重组IFN-γ可增强人单核细胞的ROI分泌能力，以及micc中腹膜巨噬细胞的ROI分泌能力和对原生动物的杀伤能力。小鼠肿瘤和某些非恶性细胞分泌的蛋白质发挥相反的作用。这种巨噬细胞失活因子 (MDF) 既可以阻断 IFN-γ 的激活诱导，又可以逆转预先存在的激活。 MDF 的作用是无毒和选择性的，抑制 ROI 的分泌，杀死细胞内的原生动物，以及 Ia 抗原的表达，而不抑制其他几种产物的分泌。或蛋白质的合成。摄入颗粒或粘附在培养容器上。 MDF 的抑制作用在去除后几天内就会逆转。 IFN-γ加速了这种逆转。鼠单核细胞分化为库普弗细胞时会严重抑制氧化代谢。即使在暴露于 IFN-γ 后，库普弗细胞分泌 ROI 和杀死细胞内原生动物的能力仍然不足。因此，可以暂时辨别巨噬细胞激活的四种状态：小鼠腹膜巨噬细胞从（a）非激活状态到（b）激活状态的转变伴随着超氧化物产生酶对NADPH的亲和力增加九倍，而细胞V,,;,或细胞色素b,,,含量没有明显增加。 MDF 诱导的小鼠腹膜巨噬细胞从激活状态转变为 (c) 失活状态，同时伴随着氧化酶 K 的增加和表观 V 的减少。佛波醇肉豆蔻酸酯乙酸酯受体数量或亲和力、葡萄糖转运、NADPH 水平没有变化。细胞色素 b,,, 含量，过氧化氢酶 (EC 1.11. 1.6) GSH。 GSH过氧化物酶 (EC 1.11. 1.9)、GSH 还原酶 (EC 1.6. 4.2) 或髓过氧化物酶，与这些细胞的 ROI 分泌能力和抗原虫活性受到抑制一致。库普弗细胞对 IFN-γ 没有反应，可能将其标记为 (d) 失活。似乎缺乏可检测的 NADPH 氧化酶活性。尽管可能存在细胞色素 hss,,。在这方面与未激活和失活的巨噬细胞不同。对这四种分化状态下的巨噬细胞的进一步生化分析可能会阐明氧化酶及其调节装置的工作原理。
Abstrutr. We are attempting to identify cytokines that regulate macrophage secretion of reactive oxygen intermediates (ROI) and to analyse the biochemical basis of their effects. In both humans and mice, interferon-y (IFN-y) appears to be the chief factor secreted by clonally unselected lymphocytes that enhances macrophage oxidative metabolism and antiprotozoal activity. In vivo administration of recombinant IFN-y enhances the ROI secretory capacity of monocytes in humans, and the secretion of ROI and killing of protozoa by peritoneal macrophages in micc. A protein secreted by murine tumours and certain non-malignant cells exerts opposing effects. This macrophage deactivation factor (MDF) both blocks the induction of activation by IFN-y and reverses pre-existent activation. MDF action is non-toxic and selective, suppressing the secretion of ROI, killing of intracellular protozoa, and expression of Ia antigen, without inhibiting secretion of several other products. or synthesis of protein. ingestion of particles or adhcrence to culture vessels. The suppressive effect of MDF is reversed over several days after its removal. This reversal is hastened by IFN-y. Profound suppression of oxidative metabolism accompanies the differentiation of murine monocytes into Kupffer cells. The capacity of Kupffer cells to secrete ROI and kill intracellular protozoa remains deficient even after exposure to IFN-y. Thus, four states of macrophage activation can provisionally be discerned: the transition of mouse peritoneal macrophages from the (a) non-activated to the (b) activated state is accompanied by a ninefold increase in affinity of the superoxide-producing enzyme for NADPH, without a marked increase in cellular V,,;,, or content of cytochrome b,,,. The MDF-induced transition of mouse peritoneal macrophages from the activated to the (c) deactivated state is accompanied by both an increase in K, and a decrease in apparent V,;,, of the oxidase. There are no changes in the phorbol myristate acetate receptor number or affinity, glucose transport, NADPH levels. cytochrome b,,, content, catalase (EC 1.11. 1.6) GSH. GSHperoxidase (EC 1.11. 1.9), GSH reductase (EC 1.6. 4.2) ormyeloperoxidase, consistent with the suppressed ROI secretory capacity and antiprotozoal activity of these cells. The Kupffer cell, whose non-responsiveness to IFN-y may mark it as (d) inactivated. appears to lack detectable NADPH oxidase activity. despite the probable presence of cytochrome hss,,. and in this regard differs from both non-activated and deactivated macrophages. Further biochemical analysis of macrophages in these four states of differentiation may illuminate the workings of the oxidase and its regulatory apparatus.