Tumor-produced, active interleukin-1β regulates gene expression in carcinoma-associated fibroblasts.
Tumor-produced, active interleukin-1β regulates gene expression in carcinoma-associated fibroblasts.
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DOI：
10.1016/j.yexcr.2011.05.023
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发表时间：
2011-09-10
影响因子：
3.7
通讯作者：
Riechelmann H
中科院分区：
文献类型：
--
作者：
Dudás J;Fullár A;Bitsche M;Schartinger V;Kovalszky I;Sprinzl GM;Riechelmann H
最近，我们描述了牙周膜（PDL）成纤维细胞和SCC-25舌鳞癌细胞的共培养模型，这导致正常成纤维细胞转化为癌相关成纤维细胞（CAFs），并在SCC-25细胞的上皮间质转化（EMT）。我们发现在正常和共培养条件下，SCC-25细胞中存在组成性高表达的白细胞介素-1 β（IL-1-β）。在我们的假设中，SCC-25中的组成性IL 1-β表达在共培养期间调节成纤维细胞中的基因表达。将PDL成纤维细胞与SCC-25细胞进行共培养，用和不用地塞米松（DEX）处理;研究IL 1-β在SCC-25细胞、肿瘤细胞和PDL成纤维细胞中的加工。Western blot和免疫细胞化学法检测IL 1 β信号通路。通过实时qPCR分析IL 1-β调节基因。SCC-25细胞产生16 kD活性IL-1-β，IL-1-β受体在PDL成纤维细胞中表达上调，诱导IL-1受体相关激酶1（IRAK-1）磷酸化和NFκB Bα核转位。干扰素调节因子1（IRF 1）、白细胞介素6（IL-6）和甘草素内过氧化物合酶2（考克斯-2）等基因在共培养过程中被诱导表达。发现IL-6和考克斯-2的诱导增强最多。用IL 1-β处理PDL成纤维细胞再现了IL 1受体、IL-6和考克斯-2的时间和剂量依赖性上调。DEX抑制IL 1-β刺激的IL-6和考克斯-2基因表达进一步证明了这一点。肿瘤细胞中IL 1-β的组成性表达导致肿瘤相关成纤维细胞中IL 1-β刺激的基因表达变化，其参与肿瘤进展。SCC-25细胞产生活性的、加工的IL 1-β。PDL成纤维细胞具有IL 1-β受体，在SCC-25肿瘤细胞存在下其表达增加4.56倍。成纤维细胞，特别是CAF中的IL 1-β受体表达代表了协调成纤维细胞和肿瘤行为的主要选择。IL-1-β信号转导中的一个关键事件，即IRAK 1的磷酸化，发生在共培养的成纤维细胞中，这导致NFκBα的核转位，并最终诱导几种基因，包括BDNF、IRF 1、IL-6和考克斯-2。发现IL-6和考克斯-2的诱导增强最多。
Recently we described a co-culture model of periodontal ligament (PDL) fibroblasts and SCC-25 lingual squamous carcinoma cells, which resulted in conversion of normal fibroblasts into carcinoma-associated fibroblasts (CAFs), and in epithelial–mesenchymal transition (EMT) of SCC-25 cells. We have found a constitutive high interleukin-1β (IL1-β) expression in SCC-25 cells in normal and in co-cultured conditions. In our hypothesis a constitutive IL1-β expression in SCC-25 regulates gene expression in fibroblasts during co-culture. Co-cultures were performed between PDL fibroblasts and SCC-25 cells with and without dexamethasone (DEX) treatment; IL1-β processing was investigated in SCC-25 cells, tumor cells and PDL fibroblasts were treated with IL1-β. IL1-β signaling was investigated by western blot and immunocytochemistry. IL1-β-regulated genes were analyzed by real-time qPCR. SCC-25 cells produced 16 kD active IL1-β, its receptor was upregulated in PDL fibroblasts during co-culture, which induced phosphorylation of interleukin-1 receptor-associated kinase-1 (IRAK-1), and nuclear translocalization of NFκBα. Several genes, including interferon regulatory factor 1 (IRF1) interleukin-6 (IL-6) and prostaglandin-endoperoxide synthase 2 (COX-2) were induced in CAFs during co-culture. The most enhanced induction was found for IL-6 and COX-2. Treatment of PDL fibroblasts with IL1-β reproduced a time- and dose-dependent upregulation of IL1-receptor, IL-6 and COX-2. A further proof was achieved by DEX inhibition for IL1-β-stimulated IL-6 and COX-2 gene expression. Constitutive expression of IL1-β in the tumor cells leads to IL1-β-stimulated gene expression changes in tumor-associated fibroblasts, which are involved in tumor progression. SCC-25 cells produce active, processed IL1-β. PDL fibroblasts possess receptor for IL1-β, and its expression is increased 4.56-times in the presence of SCC-25 tumor cells. IL1-β receptor expression in fibroblasts, especially in CAFs represents a major option in coordination of fibroblast and tumor behavior. A key event in IL1-β signaling, the phosphorylation of IRAK1, occurred in co-cultured fibroblasts, which has lead to nuclear translocation of NFκBα, and finally to induction of several genes, including BDNF, IRF1, IL-6 and COX-2. The most enhanced induction was found for IL-6 and COX-2.
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影响因子：
9.7
作者：
Higashikawa, Koichiro;Yoneda, Shingo;Kamata, Nobuyuki
通讯作者：
Kamata, Nobuyuki
影响因子：
2.7
作者：
Miyazawa, K;Mori, A;Okudaira, H
通讯作者：
Okudaira, H
影响因子：
6.2
作者：
Saha, Ramendra N.;Liu, Xiaojuan;Pahan, Kalipada
通讯作者：
Pahan, Kalipada
影响因子：
4.1
作者：
Dudás, J;Ramadori, G;Kovalszky, I
通讯作者：
Kovalszky, I
影响因子：
3.3
作者：
Gallo, O;Masini, E;Franchi, A
通讯作者：
Franchi, A