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Basic approaches for the development of immunomodulatory and anti-inflammatory drugs acting on the signaling molecules

开发作用于信号分子的免疫调节和抗炎药物的基本方法

基本信息

批准号：
16390024
负责人：
KASAHARA Tadashi
金额：
$ 6.66万
依托单位：
Kyoritsu University of Pharmacy
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390024/
关键词：
TNF signaling TRAF6 NF-kB Focal adhesion kinase DNA microarray MALDI-TOF MS Apoptosis FAK FAK過剰発現

项目摘要

Many signaling molecules have been identified which act on the IL-1 and TNFa-mediated signaling. We have studied the role of the focal adhesion kinase (FAK) and TNF receptor-associated factors (TRAF) in the cytokine signaling and apoptosis induced by various apoptosis inducing agents. This system was adopted to develop several assay systems to find new immunomodulatory and anti-inflammatory drugs. Our findings are followings.1) We found that FAK deficient MEF derived from FAK-/-mice is more susceptible to the TNFa and actinomycin D-induced apoptosis than the FAK+/-cells, indicating the anti-apoptotic role against the cell-death inducing reagents. In this study, FAK was associated with RIP, while RIP was recruited in the DISC in the FAK-/-cells (Takahashi et al. 2007).2) In addition, TRAF6-/-MEF is more sensitive to the TNFa and actinomycin-D induced cell death. In this system, reactive oxygen species (ROS) was involved in the cell-death and therefore, antioxidant reagent, BHA restored … More ROS-induced cell death. Thus, TRAF6 was involved in the ROS induced apoptosis (Ichikawa et al. 2006).Above two cell-culture systems are found to be easily applicable to the screening antioxidant reagents which protects from apoptosis-inducing conditions.3) We found that FAK-overexpressed HL-60 is resistant against apoptosis induced by the various apoptosis-inducing agents including TRAIL. In contrast, FAK-overexpressed HL-60 is reftractory to the ATRA-induced differentiation. This refactoctory condition was resulted from the hyperphosphorylation of Rb protein and subsequent the c/EBPa inactivation (Hashimoto et al. 2006).4) Glycyrrhizin (GL) and related compounds were found to regulate production of anti-inflammatory chemokines, IL-8 and eotaxin-1 in the human lung fibroblasts. In particularly, 11-deoxo-GL and Hetero-30-OH-GL were effective to inhibit IL-8 and eotaxin-1 (Matsui et al. 2004, 2006). These derivatives are now designed to be studied in in vivo assay.5) Various proteasome inhibitors were found to act differentially in the induction of eotaxin-1 and eotaxin-3 by the TNF and IL-4 in the human lung fibroblast (Rokudai et al. 2006).These study was applicable to the screening of the immunomodulatory and anti-inflammatory agents acting on the various signaling molecules. Less

已鉴定出许多信号分子作用于 IL-1 和 TNFa 介导的信号传导。我们研究了粘着斑激酶 (FAK) 和 TNF 受体相关因子 (TRAF) 在细胞因子信号转导和各种细胞凋亡诱导剂诱导的细胞凋亡中的作用。该系统被用来开发多种检测系统，以寻找新的免疫调节和抗炎药物。我们的研究结果如下：1)我们发现源自FAK-/-小鼠的FAK缺陷MEF比FAK+/-细胞更容易受到TNFa和放线菌素D诱导的细胞凋亡的影响，表明其对细胞死亡诱导剂具有抗凋亡作用。在这项研究中，FAK 与 RIP 相关，而 RIP 在 FAK-/- 细胞的 DISC 中被募集（Takahashi et al. 2007）。2) 此外，TRAF6-/-MEF 对 TNFa 和放线菌素-D 诱导的细胞死亡更敏感。在该系统中，活性氧 (ROS) 参与细胞死亡，因此抗氧化剂 BHA 可以恢复 ROS 诱导的细胞死亡。因此，TRAF6 参与了 ROS 诱导的细胞凋亡（Ichikawa et al. 2006）。发现上述两种细胞培养系统很容易适用于筛选可防止细胞凋亡诱导条件的抗氧化剂试剂。3）我们发现 FAK 过表达的 HL-60 对包括 TRAIL 在内的各种细胞凋亡诱导剂诱导的细胞凋亡具有抵抗力。相反，FAK 过表达的 HL-60 对 ATRA 诱导的分化是抵抗的。这种难解状态是由 Rb 蛋白的过度磷酸化和随后的 c/EBPα 失活引起的（Hashimoto 等人，2006）。4) 甘草甜素 (GL) 和相关化合物被发现可调节人肺成纤维细胞中抗炎趋化因子、IL-8 和嗜酸细胞趋化因子-1 的产生。特别是，11-deoxo-GL 和 Hetero-30-OH-GL 可有效抑制 IL-8 和eotaxin-1（Matsui 等人，2004 年，2006 年）。这些衍生物现在被设计用于体内测定中的研究。5) 发现各种蛋白酶体抑制剂在人肺成纤维细胞中的 TNF 和 IL-4 诱导嗜酸细胞趋化因子-1 和嗜酸细胞趋化因子-3 方面具有不同的作用(Rokudai et al. 2006)。这些研究适用于筛选作用于各种信号传导的免疫调节剂和抗炎剂。分子。较少的

项目成果

期刊论文数量（44）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Glycyrrhizin and related compounds down-regulate production of inflammatory chemokines IL-8 and eotaxin 1 in a human lung fibroblast cell line.

DOI：
10.1016/j.intimp.2004.07.023
发表时间：
2004-12-15
期刊：
International immunopharmacology
影响因子：
5.6
作者：
Matsui S;Matsumoto H;Sonoda Y;Ando K;Aizu-Yokota E;Sato T;Kasahara T
通讯作者：
Kasahara T

Differential Regulation of Eotaxin-1/CCL11 and Eotaxin-3/CCL26 Production by the TNF-□ and IL-4 stimulated Human Lung Fibroblast

TNF-□和IL-4刺激的人肺成纤维细胞对Eotaxin-1/CCL11和Eotaxin-3/CCL26产生的差异调节

DOI：
发表时间：
2006
期刊：
Biol Pharm Bull 29(6)
影响因子：
0
作者：
Rokudai R;Terui Y;Kuniyoshi R;Mishima Y;Mishima Y;Aizu-Yokota E;Sonoda Y;Kasahara T;Hatake K
通讯作者：
Hatake K

Indirubin, a Chinese antileukemia drug, enhances the neutrophilic differentiation of human promyelocyte HL-60 cells.

靛玉红是一种中国抗白血病药物，可增强人早幼粒细胞 HL-60 细胞的中性粒细胞分化。