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首页> 外文期刊>Cytokine >TNF-α induced secretion of HMGB1 from non-immune canine mammary epithelial cells (MTH53A)
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TNF-α induced secretion of HMGB1 from non-immune canine mammary epithelial cells (MTH53A)

机译：TNF-α诱导非免疫犬乳腺上皮细胞（MTH53A）分泌HMGB1

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Background: Mammary neoplasias are one of the most frequent and spontaneously occurring malignancies in dogs and humans. Due to the similar anatomy of the mammary gland in both species, the dog has become an important animal model for this cancer entity. In human breast carcinomas, the overexpression of a protein named high-mobility group box 1 (HMGB1) was reported. Cells of the immune system were described to release HMGB1 actively exerting cytokine function. Thereby it is involved in the immune system activation, tissue repair, and cell migration. Passive release of HMGB1 by necrotic cells at sites of tissue damage or in necrotic hypoxic regions of tumors induces cellular responses e.g. release of proinflammatory cytokines leading to elevated inflammatory response and neo-vascularization of necrotic tumor areas.Herein we investigated if a time-dependent stimulation with the separately applied proinflammatory cytokines TNF-α and IFN-γ can cause secretion of HMGB1 in a non-immune related HMGB1-non-secreting epithelial canine mammary cell line (MTH53A) derived from non-neoplastic tissue. Methods: The canine cell line was transfected with recombinant HMGB1 bicistronic expression vectors and stimulated after transfection with the respective cytokine independently for 6, 24 and 48. h. HMGB1 protein detection was performed by Western blot analysis and quantified a by enzyme-linked immunosorbent assay. Live cell laser scanning multiphoton microscopy of MTH53A cells expressing a HMGB1-GFP fusion protein was performed in order to examine, if secretion of HMGB1 under cytokine stimulating conditions is also visible by fluorescence imaging. Results: The observed HMGB1 release kinetics showed a clearly time-dependent manner with a peak release 24. h after TNF-α stimulation, while stimulation with IFN-γ had only small effects on the HMGB1 release. Multiphoton HMGB1 live cell microscopy showed diffuse cell membrane structure changes 29. h after cytokine-stimulation but no clear secretion of HMGB1-GFP after TNF-α stimulation was visible. Conclusion: Our results demonstrate that non-immune HMGB1-non-secreting cells of epithelial origin derived from mammary non-neoplastic tissue can be induced to release HMGB1 by single cytokine application. This indicates that tumor and surrounding tissue can be stimulated by tumor present inflammatory and necrotic cytokines to release HMGB1 acting as neo-vascularizing factor thus promoting tumor growth.
机译：背景：乳腺肿瘤是狗和人中最常见，最自然发生的恶性肿瘤之一。由于两种物种的乳腺解剖结构相似，因此狗已成为该癌症实体的重要动物模型。据报道，在人类乳腺癌中，一种名为高迁移率族框1（HMGB1）的蛋白过表达。免疫系统的细胞被描述为释放HMGB1，从而主动发挥细胞因子的功能。因此，它涉及免疫系统激活，组织修复和细胞迁移。坏死细胞在组织损伤部位或肿瘤坏死的低氧区域中被动释放HMGB1会诱导细胞反应，例如：释放促炎细胞因子导致炎症反应增强和坏死肿瘤区域的新血管形成非肿瘤组织衍生的相关HMGB1-非分泌上皮犬乳腺细胞系（MTH53A）。方法：用重组HMGB1双顺反子表达载体转染犬细胞系，并分别用各自的细胞因子转染后分别刺激6、24和48小时。 HMGB1蛋白检测通过蛋白质印迹分析进行，并通过酶联免疫吸附测定定量。为了检测在细胞因子刺激条件下HMGB1的分泌是否也通过荧光成像可见，对表达HMGB1-GFP融合蛋白的MTH53A细胞进行了活细胞激光扫描多光子显微镜检查。结果：观察到的HMGB1释放动力学表现出明显的时间依赖性，在TNF-α刺激后24. h达到峰值释放，而IFN-γ刺激对HMGB1释放影响很小。多光子HMGB1活细胞显微镜检查显示，在细胞因子刺激后29. h，弥漫性细胞膜结构改变，但在TNF-α刺激后，HMGB1-GFP没有清晰的分泌。结论：我们的结果表明，通过单细胞因子的应用可以诱导源自乳腺非肿瘤组织的上皮来源非免疫性HMGB1非分泌细胞释放HMGB1。这表明，肿瘤存在的炎性和坏死性细胞因子可以刺激肿瘤和周围组织，释放出HMGB1，作为新血管生成因子，从而促进肿瘤的生长。

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