Tumor necrosis factor-α induces interleukin-6 production via extracellular-regulated kinase 1 activation in breast cancer cells
Tumor necrosis factor-α induces interleukin-6 production via extracellular-regulated kinase 1 activation in breast cancer cells
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DOI：
10.1023/a:1024443303436
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发表时间：
2003-07-01
影响因子：
3.8
通讯作者：
Selander, KS
中科院分区：
文献类型：
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作者：
Suarez-Cuervo, C;Harris, KW;Selander, KS
白细胞介素 6 (IL-6) 和白细胞介素 11 (IL-11) 经常由乳腺癌细胞产生。这些白细胞介素促进破骨细胞形成，并可能介导乳腺癌骨转移部位的骨溶解。转化生长因子-β (TGF-β)、肿瘤坏死因子-α (TNF-α) 和白细胞介素-1β (IL-1β) 以细胞因子依赖性方式上调乳腺癌细胞中 IL-6 和 IL-11 的产生，但人们对其在乳腺癌细胞中的细胞内信号通路知之甚少。为了研究 TGF-α、TNF-α 和 IL-1α 对人 MDA-MB-231 乳腺癌细胞中 IL-6 和 IL-11 产生的调节，我们建立了稳定表达丝裂原激活蛋白激酶 p38 (p38/AF) 或 ERK1 (ERK1K71R) 显性失活 (DN) 形式的单细胞克隆。我们在此表明，虽然在亲本细胞和 pcDNA3 对照、ERK1K71R 和 p38/AF 克隆中基础细胞、TGF-α 和 IL-1α 诱导的 IL-6 产生相似，但在 ERK1K71R 克隆中 TNF-α 诱导的 IL-6 产生减弱。 TGF-β 和 IL-1β（而非 TNF-α）诱导亲本 MDA-MB-231 细胞产生 IL-11。在稳定表达 p38/AF 和 ERK1K71R 的克隆中也检测到了类似的结果，这也没有改变基础 IL-11 的产生。总之，TNF-α 诱导的 IL-6 产生是通过 MDA-MB-231 细胞中的 ERK1 激活介导的。这些观察结果可能有助于设计新的抗溶骨疗法。
Interleukin-6 (IL-6) and interleukin-11 (IL-11) are frequently produced by breast cancer cells. These interleukins promote osteoclast formation and may mediate osteolysis at the site of breast cancer bone metastases. Transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) up-regulate IL-6 and IL-11 production in a cytokine-dependent fashion in breast cancer cells, but very little is known about their intracellular signaling pathways in breast cancer cells. To study TGF-alpha, TNF-alpha and IL-1alpha regulation of IL-6 and IL-11 production in human MDA-MB-231 breast cancer cells, we established single cell clones stably expressing dominant negative (DN) forms of the mitogen-activated protein kinases p38 (p38/AF) or ERK1 (ERK1K71R). We show here, that while basal, TGF-alpha and IL-1alpha induced IL-6 production was similar in parental cells and in pcDNA3 control, ERK1K71R and p38/AF clones, TNF-alpha induced IL-6 production was blunted in the ERK1K71R clones. TGF-beta and IL-1beta, but not TNF-alpha, induced IL-11 production in parental MDA-MB-231 cells. Similar findings were detected in clones stably expressing p38/AF and ERK1K71R, which did not change basal IL-11 production either. In conclusion, TNF-alpha induced IL-6 production is mediated via ERK1 activation in MDA-MB-231 cells. These observations may be helpful in designing new anti-osteolytic therapies.