Hori K, Mihich E, Ehrke M J
Grace Cancer Drug Center, Roswell Park Memorial Institute, New York State Department of Health, Buffalo 14263.
Cancer Res. 1989 May 15;49(10):2606-14.
The purpose of this study was to determine if recombinant murine interleukin 1 beta (rMu-IL-1 beta) alone or in combination with recombinant murine gamma-interferon (rMu-IFN-gamma) could activate murine macrophages to be tumoricidal against tumor necrosis factor (TNF)-insensitive target cells and to evaluate the possible role of interleukin 1 (IL-1) in murine macrophage activation by recombinant murine tumor necrosis factor (rMu-TNF) plus rMu-IFN-gamma. rMu-IL-1 beta and rMu-TNF alone or in combination could neither directly lyse the TNF-insensitive P815 mastocytoma nor activate resident peritoneal macrophages to be tumoricidal for this target. A synergistic induction of tumoricidal macrophage activity against P815 occurred, however, when either of these monokines was combined with rMu-IFN-gamma. The tumoricidal activity obtained was transitory, and the level of activity was dependent upon the monokine concentration and the length of induction period. Murine macrophages stimulated under the same conditions used to induce tumoricidal activity with rMu-TNF plus rMu-IFN-gamma or with rMu-IL-1 plus rMu-IFN-gamma were shown to produce low concentrations of IL-1 or TNF, respectively. Thus, a bidirectional cross-induction of the production of the two monokines occurred. The monokine production was also quite transitory, and the time of peak production of the monokines (12 h) was found to precede the time of peak tumoricidal activation (24 h). Using neutralizing antisera specific for rMu-IL-1s and rMu-TNF, the cross-induced production of TNF was shown to be required for macrophage tumoricidal activation by rMu-IL-1 beta alone (TNF-sensitive targets) or in combination with rMu-IFN-gamma (TNF-insensitive targets). There was no evidence, however, that the production of IL-1 was required for macrophage activation by rMu-TNF in combination with rMu-IFN-gamma.
本研究的目的是确定重组小鼠白细胞介素1β（rMu-IL-1β）单独使用或与重组小鼠γ干扰素（rMu-IFN-γ）联合使用是否能激活小鼠巨噬细胞，使其对肿瘤坏死因子（TNF）不敏感的靶细胞具有杀肿瘤活性，并评估白细胞介素1（IL-1）在重组小鼠肿瘤坏死因子（rMu-TNF）加rMu-IFN-γ激活小鼠巨噬细胞过程中可能发挥的作用。单独或联合使用rMu-IL-1β和rMu-TNF既不能直接裂解对TNF不敏感的P815肥大细胞瘤，也不能激活驻留腹膜巨噬细胞对该靶细胞产生杀肿瘤活性。然而，当这些单因子中的任何一种与rMu-IFN-γ联合使用时，会协同诱导针对P815的杀肿瘤巨噬细胞活性。所获得的杀肿瘤活性是短暂的，活性水平取决于单因子浓度和诱导期的长短。在用于用rMu-TNF加rMu-IFN-γ或rMu-IL-1加rMu-IFN-γ诱导杀肿瘤活性的相同条件下刺激的小鼠巨噬细胞，分别显示产生低浓度的IL-1或TNF。因此，发生了两种单因子产生的双向交叉诱导。单因子的产生也是相当短暂的，并且发现单因子的峰值产生时间（12小时）先于杀肿瘤激活的峰值时间（24小时）。使用针对rMu-IL-1和rMu-TNF的中和抗血清，单独的rMu-IL-1β（TNF敏感靶细胞）或与rMu-IFN-γ联合使用（TNF不敏感靶细胞）激活巨噬细胞杀肿瘤活性需要交叉诱导产生TNF。然而，没有证据表明rMu-TNF与rMu-IFN-γ联合激活巨噬细胞需要产生IL-1。
