Onozaki K, Urawa H, Tamatani T, Iwamura Y, Hashimoto T, Baba T, Suzuki H, Yamada M, Yamamoto S, Oppenheim J J
Department of Microbiology, University of Tsukuba, Ibaraki, Japan.
J Immunol. 1988 Jan 1;140(1):112-9.
The effect was investigated of combinations of cytokines known to be cytostatic for some tumor cells, namely interleukin 1 alpha (IL-1 alpha), interferon-beta (IFN-beta), and tumor necrosis factor (TNF), on the growth and differentiation of the mouse myeloid leukemic cell line, M1, cells. IL-1 alpha, IFN-beta, and TNF by themselves are antiproliferative for M1 cells. Treatment of cells with a mixture of any two of the three cytokines resulted in at least additive growth inhibition. None of these cytokines by themselves induced differentiation of M1 cells as assessed by increased expression of Fc receptors (FcR), stimulation of phagocytic activity and by morphologic criteria. However, as little as 1 U/ml IL-1 alpha in conjunction with IFN-beta or TNF increased FcR expression, phagocytic activity and morphologic changes in addition to inhibiting the growth of M1 cells. The combination of IFN-beta and TNF did not induce differentiation, although the growth of the cells was markedly inhibited. Both TNF and lipopolysaccharide (LPS) induced the in vitro production of IFN activity by M1 cells. Furthermore, the induction of differentiation of M1 cells by a combination of IL-1 alpha with either IFN-beta, TNF, or LPS was inhibited by antibody against mouse IFN-beta. Therefore, it appears that IFN-beta provides one of the two required signals for differentiation of M1 cells by these combinations of stimulants, the other being IL-1. Furthermore, the cytostatic effect of TNF by itself on M1 cells was also partly blocked by anti-IFN-beta antibody, suggesting that IFN-beta is also involved in the growth inhibitory effect of TNF for M1 cells. In contrast, the cytostatic effect of IL-1 on M1 cells was not blocked by anti-IFN-beta antibody. In conclusion, both the cytostatic and differentiative effect of TNF appear to be mediated by IFN-beta. Thus, the combination of IL-1 and IFN-beta or inducers of IFN-beta resulted in terminal differentiation of M1 cells. Northern blot analysis using cDNAs for murine IFN-beta1 or human IFN-beta2 showed an increased expression of mRNA for IFN-beta1 but not for IFN-beta2 by stimulation with TNF or LPS, strongly suggesting that IFN-beta 1 rather than IFN-beta 2 is responsible for TNF or LPS effects.
研究了已知对某些肿瘤细胞具有细胞生长抑制作用的细胞因子组合，即白细胞介素1α（IL-1α）、干扰素-β（IFN-β）和肿瘤坏死因子（TNF）对小鼠髓性白血病细胞系M1细胞生长和分化的影响。IL-1α、IFN-β和TNF自身对M1细胞具有抗增殖作用。用这三种细胞因子中的任意两种混合处理细胞导致至少相加的生长抑制。根据Fc受体（FcR）表达增加、吞噬活性刺激和形态学标准评估，这些细胞因子自身均未诱导M1细胞分化。然而，低至1 U/ml的IL-1α与IFN-β或TNF联合使用时，除了抑制M1细胞生长外，还增加了FcR表达、吞噬活性和形态学变化。IFN-β和TNF的组合未诱导分化，尽管细胞生长受到明显抑制。TNF和脂多糖（LPS）均诱导M1细胞在体外产生IFN活性。此外，抗小鼠IFN-β抗体抑制了IL-1α与IFN-β、TNF或LPS组合对M1细胞的分化诱导作用。因此，似乎IFN-β为这些刺激物组合诱导M1细胞分化提供了两个必需信号之一，另一个是IL-1。此外，抗IFN-β抗体也部分阻断了TNF自身对M1细胞的细胞生长抑制作用，表明IFN-β也参与了TNF对M1细胞的生长抑制作用。相反，抗IFN-β抗体未阻断IL-1对M1细胞的细胞生长抑制作用。总之，TNF的细胞生长抑制和分化作用似乎均由IFN-β介导。因此，IL-1与IFN-β或IFN-β诱导剂的组合导致M1细胞终末分化。使用小鼠IFN-β1或人IFN-β2的cDNA进行的Northern印迹分析显示，TNF或LPS刺激后IFN-β1的mRNA表达增加，但IFN-β2的mRNA未增加，强烈提示IFN-β1而非IFN-β2负责TNF或LPS的作用。
