白细胞介素1α在体外可阻断雌二醇刺激的生长，并下调MCF-7乳腺癌细胞中的雌激素受体。

Interleukin 1 alpha blocks estradiol-stimulated growth and down-regulates the estrogen receptor in MCF-7 breast cancer cells in vitro.

作者信息

Danforth D N, Sgagias M K

机构信息

Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892.

出版信息

Cancer Res. 1991 Mar 1;51(5):1488-93.

PMID:1997187

Abstract

We studied the effect of interleukin 1 alpha (IL-1 alpha) on estradiol stimulation of cell growth and estrogen receptor (ER) content in MCF-7 human breast cancer cells in vitro to determine if IL-1 alpha altered cellular estradiol responsiveness. We found that IL-1 alpha blocked estradiol-stimulated growth of these cells in a dose-dependent manner (complete antagonism at 1000 units/ml: day 7 mean growth = vehicle, 47.7 micrograms DNA; estradiol 10(-10) M, 95.1; IL-1 alpha/estradiol, 44.6) and at all concentrations of estradiol from 10(-8) to 10(-11) M. IL-1 alpha in combination with trans-hydroxytamoxifen further inhibited estradiol-stimulated growth (vehicle = 44.8 micrograms DNA, estradiol = 108.3, estradiol/trans-hydroxytamoxifen = 47.8, IL-1 alpha/estradiol/trans-hydroxytamoxifen = 3.0, P less than 0.01). Inhibition with trans-hydroxytamoxifen was IL-1 alpha dose dependent (maximum = 97% at 1000 units/ml, P less than 0.01) and estradiol dose dependent (reversible with 10(-8) M estradiol, maximum inhibition at 10(-10) M estradiol). Concomitantly, IL-1 alpha down-regulated ER concentration by 38.0-43.7% (P less than 0.01) as measured by immunoreactivity or Scatchard analysis, respectively. This occurred as early as 3 h without a change in the Kd (vehicle = 0.23 nM, IL-1 alpha = 0.24 nM), persisted for at least 48 h, was dose dependent (maximum, 43.7% at 1000 units/ml, P less than 0.01), and was blocked by cycloheximide. IL-1 alpha, however, did not block estradiol stimulation of progesterone receptor content (vehicle = 221.9, IL-1 alpha = 238.9 fmol/mg protein) and did not block estradiol down-regulation of ER content. Furthermore, IL-1 alpha alone did not alter levels of ER mRNA and did not alter estradiol down-regulation of ER mRNA. These findings indicate that while IL-1 alpha antagonizes estradiol stimulation of growth and reduces ER content, its mechanism may involve other non-estrogen-regulated pathways.

摘要

我们研究了白细胞介素1α（IL-1α）对体外培养的MCF-7人乳腺癌细胞中雌二醇刺激的细胞生长及雌激素受体（ER）含量的影响，以确定IL-1α是否改变细胞对雌二醇的反应性。我们发现，IL-1α以剂量依赖的方式阻断这些细胞的雌二醇刺激生长（1000单位/毫升时完全拮抗：第7天平均生长情况为，溶剂对照组，47.7微克DNA；10⁻¹⁰ M雌二醇组，95.1；IL-1α/雌二醇组，44.6），且在10⁻⁸至10⁻¹¹ M的所有雌二醇浓度下均如此。IL-1α与反式羟基他莫昔芬联合使用进一步抑制了雌二醇刺激的生长（溶剂对照组 = 44.8微克DNA，雌二醇组 = 108.3，雌二醇/反式羟基他莫昔芬组 = 47.8，IL-1α/雌二醇/反式羟基他莫昔芬组 = 3.0，P < 0.01）。反式羟基他莫昔芬的抑制作用呈IL-1α剂量依赖性（1000单位/毫升时最大抑制率 = 97%，P < 0.01）和雌二醇剂量依赖性（10⁻⁸ M雌二醇可使其逆转，10⁻¹⁰ M雌二醇时抑制作用最大）。同时，通过免疫反应性或Scatchard分析测定，IL-1α使ER浓度分别下调38.0 - 43.7%（P < 0.01）。这种下调最早在3小时出现，Kd值无变化（溶剂对照组 = 0.23 nM，IL-1α = 0.24 nM），至少持续48小时，呈剂量依赖性（最大下调率在1000单位/毫升时为43.7%，P < 0.01），并被环己酰亚胺阻断。然而，IL-1α并不阻断雌二醇对孕激素受体含量的刺激作用（溶剂对照组 = 221.9，IL-1α = 238.9飞摩尔/毫克蛋白），也不阻断雌二醇对ER含量的下调作用。此外，单独的IL-1α不改变ER mRNA水平，也不改变雌二醇对ER mRNA的下调作用。这些发现表明，虽然IL-1α拮抗雌二醇刺激的生长并降低ER含量，但其机制可能涉及其他非雌激素调节的途径。