Suppression of hepatocyte growth factor induction by interleukin 1 and its role in the termination of liver regeneration

白细胞介素1对肝细胞生长因子诱导的抑制及其在终止肝再生中的作用

• 批准号: 13672285
• 负责人: GOHDA Eiichi
• 金额: $ 2.3万
• 依托单位: OKAYAMA UNIVERSITY
• 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-13672285/
• 关键词: Hepatocyte growth factor (HGF); Interleukin 1(IL-1); Tumor necrosis factor α (TNF-α); Cyclic AMP; Cholera toxin; Phorbol ester; Epidermal growth factor (EGF); インターロイキン1(IL-1); tumor necrosis factor α(TNF-α); MAPキナーゼ

HGF production in cultured human dermal fibroblasts is induced by PKA-activating agents such as 8-bromo-cAMP and cholera toxin, phorbol esters such as TPA, and growth factors such as EGF. HGF production in various types of cells is also stimulated by IL-1 and TNF-α. When we examined combined effects of HGF inducers, we unexpectedly found that IL-1 strongly inhibited the induction of HGF. In this study, this inhibition was characterized. HGF production in human dermal fibroblasts was induced only slightly by IL-1 α IL-1 β and TNF-α. However, IL-1 α, IL-1β and TNF-α strongly inhibited 8-bromo-cAMP- and cholera toxin-induced HGF production. Maximal inhibitions by IL-1 and TNF-α were observed at 100 pg/mL and 3 JRU/mL, respectively. The inhibitory effects of IL-1 and TNF-α were larger than that of dexamethasone and were as large as or larger than that of TGF-β. The inhibitory effects of IL-1 and TNF-α were detected at and offer 48 h of incubation. Results of Northern blot analysis showed t … More hat both IL-1 and TNF-α inhibited the up-regulation of HGF gene expression induced by cholera toxin. The inhibitory effect of IL-1 was diminished by the IL-1 receptor antagonist. HGF inductions by EGF and TPA were also suppressed by IL-1. The inhibitory effect of IL-1 on EGF-induced HGF production was smaller than that of TGF-β but larger than those of dexamethasone and rethoic acid. The signal of IL-1 is transmitted through the MAPK family cascade and the IKK cascade. The inhibitory effect of IL-1 was not diminished by NF-kB inhibitors but diminished partially by the inhibitor of either p38 or MEK and significantly by the combination of both inhibitors, suggesting that the activation of p38 and MEK-MAPK but not the activation of NF-kB is at least partly involved in the inhibitory effect of IL-1. Since IL-1 inhibits DNA synthesis in adult rat hepatocytes in primary culture, it is possible that IL-1 acts as a dual inhibitor of DNA synthesis in liver regeneration: it not only directly inhibits DNA synthesis of hepatocytes, but also suppresses production of HGF. Less

培养的人皮肤成纤维细胞中的HGF产生由PKA活化剂如8-溴-cAMP和霍乱毒素、佛波醇酯如TPA和生长因子如EGF诱导。IL-1和TNF-α也刺激各种类型细胞中的HGF产生。当我们检测HGF诱导剂的组合作用时，我们意外地发现IL-1强烈抑制HGF的诱导。在这项研究中，这种抑制的特点。IL-1 α、IL-1 β和TNF-α对人真皮成纤维细胞HGF的产生只有轻微的诱导作用。而IL-1 α、IL-1β和TNF-α则强烈抑制8-溴-cAMP和霍乱毒素诱导的HGF生成。分别在100 pg/mL和3 JRU/mL浓度下观察到IL-1和TNF-α的最大抑制作用。IL-1和TNF-α的抑制作用大于地塞米松，与TGF-β相当或大于TGF-β。IL-1和TNF-α在孵育48 h时检测其抑制作用。北方印迹分析结果表明， ...更多信息 IL-1和TNF-α均能抑制霍乱毒素诱导的HGF基因表达上调。IL-1受体拮抗剂可减弱IL-1的抑制作用。EGF和TPA诱导的HGF也被IL-1抑制。IL-1对EGF诱导的HGF生成的抑制作用小于TGF-β，但大于地塞米松和视黄酸。IL-1的信号通过MAPK家族级联和IKK级联传递。IL-1的抑制作用不被NF-kB抑制剂减弱，但被p38或MEK的抑制剂部分减弱，并且被两种抑制剂的组合显著减弱，这表明p38和MEK-MAPK的激活而不是NF-kB的激活至少部分参与IL-1的抑制作用。由于IL-1抑制原代培养的成年大鼠肝细胞中的DNA合成，因此IL-1可能在肝再生中充当DNA合成的双重抑制剂：它不仅直接抑制肝细胞的DNA合成，而且抑制HGF的产生。少

项目成果

合田榮一: "肝細胞増殖因子(HGF)の機能と産生制御"日本薬理学雑誌. 119巻5号. 287-294 (2002)

Eiichi Goda：“肝细胞生长因子（HGF）的功能和产生控制”日本药理学杂志，第 119 卷，第 5 期。287-294（2002）

Eiichi Gohda: "Suppression of hepotocyte growth factor induction in human dermal fibroblasts by tumor necrosis factor-α"Proceedings of the Third International Symposium on Recent Advances in Inflammation Research. (Kyongsan,Korea). 53-55 (2002)

Eiichi Gohda：“肿瘤坏死因子-α 对人真皮成纤维细胞中肝细胞生长因子诱导的抑制”，第三届国际炎症研究最新进展研讨会论文集（韩国庆山）。

Eiichi Gohda: "Suppression of hepatocyte growth factor induction in human dermal fibroblasts by tumor necrosis factor-α"Proceedings of the Third International Symposium on Recent Advances in Inflammation Research (Kyongsan, Korea). 53-55 (2002)

Eiichi Gohda：“肿瘤坏死因子-α 对人真皮成纤维细胞中肝细胞生长因子诱导的抑制”第三届国际炎症研究最新进展研讨会论文集（韩国庆山）53-55（2002 年）。

合田榮一: "肝細胞増殖因子(HGF)の機能と産生制御"日本薬理学雑誌. 119巻5号(掲載予定). (2002)

Eiichi Goda：“肝细胞生长因子（HGF）的功能和产生控制”，日本药理学杂志，第 119 卷，第 5 期（待出版）。

Ejichi Gohda: "Suppression of hepatocyte growth factor induction in human dermal fibroblasts by tumor necrosis factor-α"Proceedings of the Third International Symposium on Recent Advances in Inflammation Research(Kyongsan, Korea). 53-55 (2002)

Ejichi Gohda：“肿瘤坏死因子-α 对人真皮成纤维细胞中肝细胞生长因子诱导的抑制”第三届国际炎症研究最新进展研讨会论文集（韩国庆山）53-55（2002 年）。