Leu R W, Leu N R, Shannon B J, Fast D J
Biomedical Division, Samuel Roberts Noble Foundation, Inc., Ardmore, OK 73402.
J Immunol. 1991 Sep 15;147(6):1816-22.
IFN-gamma primes murine macrophages to render them responsive for triggering by subactivating concentrations of bacterial LPS to mediate nonspecific tumor cytotoxicity. However, IFN-gamma also has direct anti-proliferative effects on transformed cells that serve as sensitive tumor targets for cytotoxic macrophages. We investigated the effects of preexposure of L1210 mouse leukemia and P815 mouse mastocytoma targets to rIFN-gamma on changes in their susceptibility to cytotoxicity by LPS-activated mouse peritoneal macrophages (PM). Co-incubation of inflammatory PM and either L1210 or P815 targets with IFN-gamma and LPS produced a classical synergistic cytotoxicity for both targets over that of IFN-gamma or LPS alone. Similar synergistic augmentation of cytotoxicity occurred when effector PM were preprimed for 24 h with IFN-gamma before testing for cytotoxicity of untreated targets. However, pretreatment of L1210 and P815 targets for 24 h with IFN-gamma (50 U) before assay produced divergent results in that L1210 was more susceptible, whereas P815 was less susceptible to cytotoxicity by LPS-activated macrophages. Similar results were obtained when both macrophages and targets were pretreated separately with IFN-gamma for 24 h before their combined assay for tumor cytotoxicity. Pretreatment of L1210 targets for 1, 4, or 24 h with IFN-gamma produced similar effects on their increased susceptibility to macrophage cytotoxicity. In contrast, P815 pretreated for 1 and 4 h with IFN-gamma showed an early increased susceptibility to macrophage cytotoxicity followed by a decrease after 24 h pretreatment. The pretreatment of L1210 or P815 targets with IFN-gamma before their exposure to LPS-activated macrophages had no effect on the production of TNF. However, there was a corresponding increase in nitric oxide generation by LPS-activated macrophages after their exposure to IFN-gamma pretreated L1210 targets and a decrease in the presence of IFN-gamma-pretreated P815 targets that correlated with their changes in susceptibility to macrophage killing. Nitric oxide generation by macrophages alone in response to LPS was found to be greater than when effector macrophages were exposed to the tumor targets and this was either increased by L1210 or decreased by P815 that had been pretreated with IFN-gamma. Our results indicate that IFN-gamma may act directly and differentially on tumor targets to alter their susceptibility for macrophage cytotoxicity, which was coupled to changes in the generation of cytotoxic nitric oxide, rather than TNF production by the macrophage.(ABSTRACT TRUNCATED AT 400 WORDS)
γ干扰素使小鼠巨噬细胞致敏，使其能对亚激活浓度的细菌脂多糖（LPS）触发产生反应，从而介导非特异性肿瘤细胞毒性。然而，γ干扰素对转化细胞也有直接的抗增殖作用，这些转化细胞是细胞毒性巨噬细胞的敏感肿瘤靶点。我们研究了将L1210小鼠白血病细胞和P815小鼠肥大细胞瘤靶点预先暴露于重组γ干扰素（rIFN-γ）对其对LPS激活的小鼠腹腔巨噬细胞（PM）细胞毒性敏感性变化的影响。炎性PM与L1210或P815靶点以及γ干扰素和LPS共同孵育，对这两种靶点均产生了经典的协同细胞毒性，其效果超过单独使用γ干扰素或LPS。当效应性PM在测试未处理靶点的细胞毒性之前用γ干扰素预致敏24小时时，也出现了类似的细胞毒性协同增强。然而，在测定前用γ干扰素（50 U）对L1210和P815靶点进行24小时预处理产生了不同的结果，即L1210对LPS激活的巨噬细胞的细胞毒性更敏感，而P815则较不敏感。当巨噬细胞和靶点在联合测定肿瘤细胞毒性之前分别用γ干扰素预处理24小时时，也得到了类似的结果。用γ干扰素对L1210靶点进行1、4或24小时预处理，对其增加对巨噬细胞细胞毒性的敏感性产生了类似的影响。相比之下，用γ干扰素预处理1小时和4小时的P815显示出对巨噬细胞细胞毒性的早期敏感性增加，随后在预处理24小时后敏感性降低。在L1210或P815靶点暴露于LPS激活的巨噬细胞之前用γ干扰素进行预处理，对肿瘤坏死因子（TNF）的产生没有影响。然而，LPS激活的巨噬细胞在暴露于γ干扰素预处理的L1210靶点后，一氧化氮生成相应增加，而在存在γ干扰素预处理的P815靶点时一氧化氮生成减少，这与它们对巨噬细胞杀伤敏感性的变化相关。发现巨噬细胞单独对LPS产生的一氧化氮生成量大于效应性巨噬细胞暴露于肿瘤靶点时的生成量，并且这一量在L1210预处理后增加，而在P815预处理后减少。我们的结果表明，γ干扰素可能直接且有差异地作用于肿瘤靶点，以改变它们对巨噬细胞细胞毒性的敏感性，这与细胞毒性一氧化氮生成的变化相关，而不是与巨噬细胞产生TNF相关。（摘要截短至400字）
