Toi M, Bicknell R, Harris A L
Imperial Cancer Research Fund, University of Oxford, John Radcliffe Hospital, England.
Cancer Res. 1992 Jan 15;52(2):275-9.
Within human carcinomas, there is often an infiltration of lymphocytes and other cells of the immune system. A variety of cytokines are produced by such cells that could have a paracrine influence on the growth of tumor epithelium. The effect of one of these cytokines, interleukin-4 (IL-4), on human breast and colon cancer cell lines was therefore examined. IL-4 inhibited the growth of human colon (HT 29) and breast [MCF-7 wild type (MCF-7 WT), MCF-7 Adriamycin-resistant (MCF-7r), MDA-MB-231, and MDA-MB-468] carcinoma cells in culture. Competitive binding of 125I-IL-4 demonstrated the presence of 2000 high affinity IL-4-binding sites on HT 29 cells. The Kd for specific binding of 125I-IL-4 to HT 29 cells was 77 pM. Further studies were conducted on the estrogen-dependent MCF-7 WT and estrogen-independent MDA-MB-231 breast carcinoma lines. Concentrations of IL-4 of 10-100 nM were required to significantly inhibit growth of these carcinoma cell lines; e.g., with MCF-7 WT cells, half-maximal inhibition of growth occurred at 20 nM IL-4. Specific binding of 125I-IL-4 was detected to MCF-7 WT and MDA-MB-231 cells, but the low level of binding precluded Scatchard analysis. IL-4 inhibited 90% of the 17 beta-estradiol-stimulated growth of MCF-7 WT cells in a dose-dependent manner but without a change in estrogen receptor expression. Inhibition of growth by IL-4 was less in the absence of estrogens. Combined treatment with IL-4 and other known inhibitors of breast carcinoma cell growth [transforming growth factor-beta 1 (TGF-beta 1) and the antiestrogen tamoxifen] showed additive inhibition. The hormone-independent cell lines MCF-7r and MDA-MB-231 were additively inhibited by IL-4 and TGF-beta 1. This was not the case with MDA-MB-468 cells in which inhibition by IL-4 and TGF-beta 1 was of similar magnitude but no significantly greater effect was observed on combined treatment. No secretion of IL-4 was detected from these cell lines either basally or on treatment with TGF-beta 1 or tamoxifen, and we conclude that IL-4 is a nonautocrine inhibitor of breast carcinoma cell growth.
在人类癌症中，通常存在淋巴细胞和免疫系统其他细胞的浸润。这些细胞会产生多种细胞因子，它们可能对肿瘤上皮细胞的生长产生旁分泌影响。因此，研究了其中一种细胞因子白细胞介素-4（IL-4）对人乳腺癌和结肠癌细胞系的作用。IL-4抑制培养的人结肠（HT 29）和乳腺癌细胞[MCF-7野生型（MCF-7 WT）、MCF-7阿霉素耐药型（MCF-7r）、MDA-MB-231和MDA-MB-468]的生长。125I-IL-4的竞争性结合表明HT 29细胞上存在2000个高亲和力的IL-4结合位点。125I-IL-4与HT 29细胞特异性结合的解离常数（Kd）为77 pM。对雌激素依赖的MCF-7 WT和雌激素非依赖的MDA-MB-231乳腺癌细胞系进行了进一步研究。需要10 - 100 nM的IL-4浓度才能显著抑制这些癌细胞系的生长；例如，对于MCF-7 WT细胞，在20 nM IL-4时生长抑制达到半数最大抑制。检测到125I-IL-4与MCF-7 WT和MDA-MB-231细胞有特异性结合，但结合水平较低，无法进行Scatchard分析。IL-4以剂量依赖的方式抑制MCF-7 WT细胞90%的17β-雌二醇刺激的生长，但不改变雌激素受体的表达。在没有雌激素的情况下，IL-4对生长的抑制作用较小。IL-4与其他已知的乳腺癌细胞生长抑制剂[转化生长因子-β1（TGF-β1）和抗雌激素他莫昔芬]联合治疗显示出相加抑制作用。激素非依赖的细胞系MCF-7r和MDA-MB-231被IL-4和TGF-β1相加抑制。MDA-MB-468细胞则不然，其中IL-4和TGF-β1的抑制作用程度相似，但联合治疗未观察到显著更大的效果。这些细胞系在基础状态下或用TGF-β1或他莫昔芬处理后均未检测到IL-4的分泌，我们得出结论，IL-4是乳腺癌细胞生长的非自分泌抑制剂。
