Role of ornithine decarboxylase in the regulation of cell growth by IL-1 and tumor necrosis factor.
Role of ornithine decarboxylase in the regulation of cell growth by IL-1 and tumor necrosis factor.
复制标题
鸟氨酸脱羧酶在 IL-1 和肿瘤坏死因子调节细胞生长中的作用。
作者：
Y. Endo;K. Matsushima;K. Onozaki;J. Oppenheim
鸟氨酸脱羧酶（ODC）是多胺合成的限速酶，而多胺是细胞生长所必需的。作为阐明IL-1的作用机制的方法，在其增殖被IL-1抑制或增强的各种细胞系中检查IL-1对ODC活性的影响。在这些实验中使用的所有细胞类型的增殖显着抑制由特定的ODC抑制剂，α-二氟甲基鸟氨酸（DFMO），证实了细胞增殖的ODC活性的关键作用。在IL-1对其发挥抗增殖作用的那些细胞中，如人黑素瘤细胞系（A375）和恶性人乳腺细胞系（MCF-7和T-47 D），IL-1也显著抑制ODC活性。另一方面，ODC活性在响应于IL-1而被刺激增殖的细胞中被刺激，例如小鼠辅助T细胞系（D10.G4.1）、NK细胞样细胞系（YT）和人胶质母细胞瘤细胞系（U373 MG）。IL-1对ODC活性的作用先于其对DNA合成的作用，并以剂量依赖性方式与其对DNA合成的作用直接相关。此外，腐胺，ODC反应的产物和多胺的前体，能够克服大多数，但不是全部，IL-1在A375黑色素瘤细胞，这是最敏感的抑制IL-1的抗增殖作用。然而，腐胺并不能逆转IL-1对MCF-7和T-47 D细胞系的细胞生长抑制作用。与此相反，腐胺，像IL-1，表现出一定的共促有丝分裂活性的D10.G4.1细胞。由于TNF和IL-1的生物学活性显示出相当大的重叠，因此还检测了TNF对ODC活性的影响。TNF对A375细胞有抗增殖作用，对U373 MG细胞有促增殖作用。TNF可抑制A375细胞ODC活性，而刺激U373 MG细胞ODC活性。腐胺也部分克服了TNF的抑制作用。这些结果表明，ODC活性的调节可能是IL-1和TNF在某些肿瘤细胞类型中的抗增殖和增殖作用的关键组成部分。
Ornithine decarboxylase (ODC) is a rate-limiting enzyme in polyamine synthesis, and polyamines are required for cell growth. As an approach to clarifying the mechanism of action IL-1, the effects of IL-1 on ODC activity were examined in various cell lines whose proliferation was either suppressed or enhanced by IL-1. The proliferation of all cell types used in these experiments was markedly suppressed by a specific ODC inhibitor, alpha-difluoromethyl ornithine (DFMO), substantiating the crucial role of ODC activity for cell proliferation. ODC activity also was considerably suppressed by IL-1 in those cells on which IL-1 exerts an antiproliferative effect, such as a human melanoma cell line (A375) and malignant human mammary cell lines (MCF-7 and T-47D). On the other hand, ODC activity was stimulated in cells that are stimulated to proliferate in response to IL-1, such as a mouse helper T cell line (D10.G4.1), a NK cell-like cell line (YT), and a human glioblastoma cell line (U373 MG). The effect of IL-1 on ODC activity preceded and directly correlated in a dose-dependent manner with its effect on DNA synthesis. Furthermore, putrescine, a product of the ODC reaction and a precursor of polyamines, was able to overcome most, but not all, the antiproliferative action of IL-1 in A375 melanoma cells, which were the most sensitive to suppression by IL-1. However, putrescine did not reverse the cytostatic effect of IL-1 on MCF-7 and T-47D cell lines. In contrast, putrescine, like IL-1, exhibited some co-mitogenic activity on D10.G4.1 cells. Because the biological activities of TNF and IL-1 show considerable overlap, the effect of TNF on ODC activity also was examined. TNF had an antiproliferative effect on A375 cells and stimulated the proliferation of U373 MG cells. The ODC activity in A375 cells was suppressed by TNF, and the ODC activity in U373 MG cells was stimulated by TNF. Putrescine also partially overcame the inhibitory effect of TNF. These results suggest that the regulation of ODC activity may be a key component in the antiproliferative and proliferative action of IL-1 and TNF in some tumor cell types.