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Induction of EGF-like Growth Factors and Epidermal Growth Factor Receptors by Interleukin-1β in Gastric Mucosa

胃粘膜中白介素-1β诱导EGF样生长因子和表皮生长因子受体

基本信息

批准号：
13670570
负责人：
WADA Ken
金额：
$ 2.24万
依托单位：
Nippon Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670570/
关键词：
IL-1 TGF-α EGF-like growth factor gastritis gastric fibroblast Interleukin-1β

项目摘要

In this sturdy, we hypothesized IL-1β, proinflammatory cytokine, could exert some biological effects through expression of epidermal growth factor (EOF) family peptides in gastric mucosa. Therefore we examined the ability of IL-1β to induce EGF-like growth factors and EGF receptor (EGFR) in human gastric fibrodasts and 5 gastric cancer cell lines. Methods: Cultured cells were stimulated by IL-1β and the mRNA expression of transforming growth factor-α (TGF-α), heparin-binding EGF-like growth factor (HB-EGF) and amphiregulin (AR) was examined by real-time PCR. TGF-α in the conditioned media (CM) obtained from culture cells was determined using a TGF-α ELISA kit. EGFR expression was examined by western blot analysis. Results: IL-1β increased mRNA levels of TGF-α, HB-EGF and AR in 4 gastric cancer cell lines. In contrast, a significant expression of TGF-α mRNA was not found in gastric fibroblasts. In the 4 gastric cancer cell lines, IL-1β stimulated TGF-α release into CM only in the presen … More ce of 12-myristate 13-acetate (PMA), which is known to induce a cleavaging enzyme of proTGF-α. Selective COX-2 inhibitors did not inhibit the TGF-α release by IL-1β, suggesting that this induction of TGF-α was not mediated by COX-2. Furthermore, IL-1β increased TGF-α expression more significantly in coculture of MKN28 cells and gastric fibroblasts than in separate cultivation, indicating there might be some epithelial-mesenchymal interaction in TGF-α induction by IL-1β. CM from gastric fibroblasts incubated with IL-1β stimulated TGF-α expression in MKN28 cells more significantly than control media, confirming our assumption. Contrary to TGF-α expression, IL-1β increased expression of EGFR in gastric fibroblasts, but not in MKN28 cells. Furthermore, IL-1β activated tyrosine phosphorylation of EGFR in coculture of MKN28 cells and gastric fibroblasts more markedly than in separate cultivation. Conclusion: IL-1β exerts its biological effects on the gastric mucosa through the induction of EGFR and EGF-like growth factors in epithelial-mesenchymal interaction. Less

因此，我们推测IL-1β是一种促炎细胞因子，可能通过表达表皮生长因子（epidermal growth factor，EGF）家族多肽发挥其生物学效应。因此，我们检测了IL-1β诱导人胃纤维化细胞和5种胃癌细胞系中EGF样生长因子和EGF受体（EGFR）的能力。研究方法：用IL-1β刺激培养细胞，实时荧光定量PCR检测转化生长因子-α（TGF-α）、肝素结合表皮生长因子样生长因子（HB-EGF）和双调蛋白（AR）mRNA的表达。用TGF-α ELISA试剂盒测定培养细胞的条件培养基（CM）中TGF-α的含量。免疫印迹法检测EGFR表达。结果：IL-1β可上调4种胃癌细胞系TGF-α、HB-EGF和AR的mRNA水平。而胃成纤维细胞TGF-α mRNA无明显表达。在4种胃癌细胞系中，IL-1β刺激TGF-α释放到CM中，仅在存在IL-1 β的细胞中。 ...更多信息 12-肉豆蔻酸酯13-乙酸酯（PMA），其已知诱导proTGF-α的裂解酶。选择性考克斯-2抑制剂不抑制IL-1β对TGF-α的释放，表明这种TGF-α的诱导不是由考克斯-2介导的。IL-1β对MKN-28细胞和胃成纤维细胞TGF-α表达的促进作用明显高于单独培养，提示IL-1β诱导TGF-α表达可能存在上皮-间质相互作用。与对照培养基相比，来自与IL-1β孵育的胃成纤维细胞的CM更显著地刺激MKN 28细胞中TGF-α的表达，证实了我们的假设。与TGF-α表达相反，IL-1β增加胃成纤维细胞中EGFR的表达，但不增加MKN 28细胞中EGFR的表达。IL-1β在MKN-28细胞与胃成纤维细胞共培养中对EGFR酪氨酸磷酸化的激活作用明显高于单独培养。结论：IL-1β通过诱导EGFR和EGF样生长因子在上皮-间质相互作用中发挥其生物学作用。少