Schlager S I, Madden L D, Meltzer M S, Bara S, Mamula M J
Cell Immunol. 1983 Apr 1;77(1):52-68. doi: 10.1016/0008-8749(83)90006-0.
Peritoneal macrophages (M phi) from mice became cytotoxic after incubation with lymphokine (LK); tumoricidal activity was evident with M phi treated with LK for 4 hr, became maximal after 8-12 hr of incubation, and decreased to control levels by 24-36 hr. LK induced marked changes in M phi lipid composition: cellular content of cholesterol (CHOL) and polyunsaturated fatty acid (UFA) content of cellular lipids (especially 18:3) increased two- to threefold after 8 hr when the cells showed maximal tumoricidal activity. Cellular lipid and fatty-acid content returned to control levels by 24 hr when the M phi had lost tumoricidal activity. These changes were not observed with equal numbers of M phi cultured in control supernatants. To analyze the role of CHOL and UFA in M phi tumor cytotoxicity, casein-induced peritoneal M phi were enriched in CHOL or linolenic acid (18:3) and then tested for their ability to kill 1023 tumor cells. The 18:3-enriched cells were markedly tumoricidal, whereas controls cultured in delipidized medium alone or enriched with saturated fatty acid (18:0) were not cytotoxic. CHOL-enriched M phi were not tumoricidal; indeed, these cells were inhibited in their killing after treatment with LK compared to M phi cultured in delipidized medium with LK alone. The effects of 18:3 and CHOL enrichment of the M phi on their metabolic status, inflammatory function, and tumor cell-binding capacity were tested. The 18:3-enriched M phi were depressed in their ability to synthesize protein and in phagocytic activity compared to controls; these cells showed a transient increase in superoxide release. M phi cultured with 18:3 for 48 hr were also cytotoxic for P815 tumor cells, but did not show an enhanced capacity for P815 binding compared to controls. CHOL-enriched M phi were similar to control cells in their protein synthesizing and phagocytic activities; these cells also showed an early transient increase in superoxide release. CHOL-enriched M phi were not cytotoxic for P815 cells, but bound the tumor cells more readily than did the 18:3-enriched M phi. The data suggest that endogenous levels of 18:3 and CHOL can regulate M phi tumor cytotoxicity, but not through regulation of M phi protein synthesis, oxidative metabolism, or augmented capacity for tumor target binding.
小鼠腹腔巨噬细胞（M phi）与淋巴因子（LK）孵育后具有细胞毒性；用LK处理4小时的M phi即表现出明显的杀肿瘤活性，孵育8 - 12小时后活性达到最大值，24 - 36小时后降至对照水平。LK诱导M phi脂质组成发生显著变化：当细胞表现出最大杀肿瘤活性时，8小时后细胞内胆固醇（CHOL）含量和细胞脂质中的多不饱和脂肪酸（UFA）含量（尤其是18:3）增加了两到三倍。当M phi失去杀肿瘤活性时，24小时后细胞脂质和脂肪酸含量恢复到对照水平。在对照上清液中培养等量的M phi未观察到这些变化。为了分析CHOL和UFA在M phi肿瘤细胞毒性中的作用，用酪蛋白诱导的腹腔M phi富集CHOL或亚麻酸（18:3），然后检测它们杀伤1023肿瘤细胞的能力。富含18:3的细胞具有明显的杀肿瘤活性，而单独在脱脂培养基中培养或富含饱和脂肪酸（18:0）的对照细胞则无细胞毒性。富含CHOL的M phi没有杀肿瘤活性；实际上，与仅在脱脂培养基中与LK一起培养的M phi相比，这些细胞在用LK处理后的杀伤能力受到抑制。检测了M phi中18:3和CHOL富集对其代谢状态、炎症功能和肿瘤细胞结合能力的影响。与对照相比，富含18:3的M phi合成蛋白质的能力和吞噬活性降低；这些细胞的超氧化物释放短暂增加。用18:3培养48小时的M phi对P815肿瘤细胞也具有细胞毒性，但与对照相比，其对P815的结合能力并未增强。富含CHOL的M phi在蛋白质合成和吞噬活性方面与对照细胞相似；这些细胞的超氧化物释放也早期短暂增加。富含CHOL的M phi对P815细胞无细胞毒性，但比富含18:3的M phi更容易结合肿瘤细胞。数据表明，18:3和CHOL的内源性水平可调节M phi肿瘤细胞毒性，但不是通过调节M phi蛋白质合成、氧化代谢或增强肿瘤靶标结合能力来实现的。
