Urban J L, Shepard H M, Rothstein J L, Sugarman B J, Schreiber H
Proc Natl Acad Sci U S A. 1986 Jul;83(14):5233-7. doi: 10.1073/pnas.83.14.5233.
Activated macrophages (aM phi) destroy more effectively cancer cells than normal cells. The mechanism by which macrophages destroy cancer cells is not known. We report here that tumor cells susceptible to aM phi were killed by recombinant (r) tumor necrosis factor type alpha (TNF-alpha), whereas variant tumor cells resistant to aM phi after selection in vitro or in vivo were resistant to killing by rTNF-alpha. The converse selection for rTNF-alpha-resistant variants resulted in cells that were also resistant to killing by aM phi. The sensitivity of macrophage-resistant variants was not changed to other tumoricidal cells or soluble mediators, except that the macrophage-resistant variants were also resistant to the effects of another cytotoxic protein, B-cell lymphotoxin, which is structurally related to rTNF-alpha. Similar results were obtained regardless of whether short-term or long-term cytotoxic effects of aM phi were measured. Finally, it was shown that killing of tumor cells by murine aM phi was completely inhibited with a polyclonal antibody that neutralizes the effects of murine TNF-alpha. These results suggest a major role for TNF-alpha in tumor cell destruction by aM phi in vitro and in vivo.
活化巨噬细胞（aM phi）对癌细胞的破坏作用比正常细胞更有效。巨噬细胞破坏癌细胞的机制尚不清楚。我们在此报告，对aM phi敏感的肿瘤细胞可被重组（r）肿瘤坏死因子α（TNF-α）杀死，而在体外或体内筛选后对aM phi具有抗性的变异肿瘤细胞对rTNF-α的杀伤具有抗性。对rTNF-α抗性变异体进行反向筛选得到的细胞对aM phi的杀伤也具有抗性。除了巨噬细胞抗性变异体对另一种细胞毒性蛋白B细胞淋巴毒素的作用也具有抗性（B细胞淋巴毒素在结构上与rTNF-α相关）外，巨噬细胞抗性变异体对其他杀肿瘤细胞或可溶性介质的敏感性未发生改变。无论测量的是aM phi的短期还是长期细胞毒性作用，均可获得类似结果。最后，结果表明，用一种中和鼠TNF-α作用的多克隆抗体可完全抑制鼠aM phi对肿瘤细胞的杀伤。这些结果表明TNF-α在体外和体内aM phi对肿瘤细胞的破坏中起主要作用。
