Gooch J L, Lee A V, Yee D
Department of Medicine, University of Texas Health Science Center, San Antonio 78284-7884, USA.
Cancer Res. 1998 Sep 15;58(18):4199-205.
Interleukin-4 (IL-4) is a pleiotropic cytokine produced by mast cells and T lymphocytes that promotes proliferation and immunoglobulin class-switching in B cells. IL-4 receptors (IL-4Rs) are also expressed by nonhematopoietic cells as well as some tumor cells. Unlike its mitogenic effect on B cells, IL-4 inhibits the growth of some cancer cells in vitro. In this study, we show that IL-4R is expressed by breast and ovarian cancer cell lines. Furthermore, anchorage-dependent and -independent growth of breast cancer cell lines MCF-7 and MDA-MB-231 is inhibited by IL-4 treatment, and this effect requires IL-4R. Interestingly, IL-4 only inhibited proliferating breast cancer cells and had no effect on basal, unstimulated growth. We therefore characterized the effect of IL-4 on breast cancer cell growth stimulated by either estradiol or insulin-like growth factor I (IGF-I). In both anchorage-dependent and -independent growth assays, IL-4 inhibited estradiol-stimulated growth. The antiestrogen effect of IL-4 was not due to IL-4 interference with the estrogen receptor, because IL-4 did not interfere with estrogen receptor-mediated reporter gene transactivation. In contrast, IL-4 had no effect on IGF-I-stimulated proliferation. Because IGF-I is known to inhibit programmed cell death, we examined apoptosis as a possible mechanism of IL-4 action. We established that IL-4 induced apoptosis in breast cancer cells by five independent criteria: (a) morphological indicators including pyknotic nuclei and cytoplasmic condensation; (b) DNA fragmentation; (c) the formation of DNA laddering; (d) the cleavage of poly(ADP-ribose) polymerase; and (e) the presence of cells with sub-G1 DNA content. IL-4 increased the percentage of apoptotic cells in MCF-7 and MDA-MB-231 cells 6.0- and 6.7-fold over that of the control, respectively. Finally, the addition of IGF-I reversed IL-4-induced apoptosis, suggesting that the mechanism of IL-4-induced growth inhibition in human breast cancer cells is the induction of programmed cell death.
白细胞介素-4（IL-4）是一种由肥大细胞和T淋巴细胞产生的多效性细胞因子，可促进B细胞增殖和免疫球蛋白类别转换。非造血细胞以及一些肿瘤细胞也表达IL-4受体（IL-4Rs）。与它对B细胞的促有丝分裂作用不同，IL-4在体外可抑制某些癌细胞的生长。在本研究中，我们发现乳腺癌和卵巢癌细胞系表达IL-4R。此外，IL-4处理可抑制乳腺癌细胞系MCF-7和MDA-MB-231的贴壁依赖性和非贴壁依赖性生长，且该效应需要IL-4R。有趣的是，IL-4仅抑制增殖的乳腺癌细胞，对基础的、未受刺激的生长无影响。因此，我们研究了IL-4对由雌二醇或胰岛素样生长因子I（IGF-I）刺激的乳腺癌细胞生长的影响。在贴壁依赖性和非贴壁依赖性生长试验中，IL-4均抑制雌二醇刺激的生长。IL-4的抗雌激素作用并非由于其干扰雌激素受体，因为IL-4不干扰雌激素受体介导的报告基因反式激活。相反，IL-4对IGF-I刺激的增殖无影响。由于已知IGF-I可抑制程序性细胞死亡，我们将凋亡作为IL-4作用的一种可能机制进行研究。我们通过五个独立标准确定IL-4可诱导乳腺癌细胞凋亡：（a）形态学指标，包括核固缩和细胞质浓缩；（b）DNA片段化；（c）DNA梯形条带的形成；（d）聚（ADP-核糖）聚合酶的裂解；（e）存在亚G1期DNA含量的细胞。IL-4使MCF-7和MDA-MB-231细胞中凋亡细胞的百分比分别比对照增加了6.0倍和6.7倍。最后，添加IGF-I可逆转IL-4诱导的凋亡，提示IL-4诱导人乳腺癌细胞生长抑制的机制是诱导程序性细胞死亡。
