Study on the action mechanism of IL-1 and its regulation

IL-1作用机制及其调控研究

• 批准号: 14370750
• 负责人: ONOZAKI Kikuo
• 金额: $ 8.26万
• 依托单位: Nagoya City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370750/
• 关键词: IL-1; IL-1 receptor; cytokine; TLR; sialic acid; TRB3; TGFβ; メラノーマ; 細胞増殖; TLR; インターロイキンレセプター; アンチザイム

IL-1 plays an important role in host reactions, including immunologic, inflammatory and hematologic reactions, and in regulation of cell proliferation and differentiation. Therefore, it is important to elucidate the mechanism of EL-1 action, production and its regulation. In this study we studied the many aspects of IL-1 action and its regulatory mechanisms.1) IL-1 signaling. We analyzed the mechanism of IL-1 action leading to the inhibition of cell proliferation of A375 human melanoma cells. We discovered a novel protein TRB3 in the downstream of CHOP, which is regulated by p38 MAPK By the analysis of the promoter region of TRB3 gene, CHOP-ATP region appeared to be important for the gene activation. Furthermore, TRB3 inhibited the transcriptional activity of CHOP.2) IL-1 receptor family. Toll like receptors, the IL-1 family, are known to be signaling molecule for bacteria and synthetic oligonudeotide. We found that IL-1 augments the expression and gene activation of TLR2 in mouse hepa … More tocytes. TGFR down regulated the IL-1-induced TLR2 expression by down-regulation the IL-1 induced up-regulation of IL-1 receptor type I(IL--1RI). TGFβ also inhibited the IL-1 induced IL-1RI expression in human fibroblasts.3) Gene expression mechanism of IL-1α: A375R8 cells constitutively produce IL-1α. We found that GC-rich region of the IL-1α gene promoter is important for the constitutive gene activation. Furthermore, the binding of Sp1 to the GC rich region and an association of Sp1 and HDAC1 are important for the IL-1α gene activation. Estrogen induced the activation of IL-1α promoter activity via estrogen receptor a in human rheumatoid arthritis patient-derived fibroblast like synovial cells.4) Carbohydrate conjugated IL-1: Sialic acid or sialylgalactose with C9 arm was conjugated to human IL-1α. In vitro activity of the carbohydrate-conjugated IL-1α generally exhibited the reduction in its biological activities in vitro. However, the carbohydrate-conjugated IL-1α exhibited selective activities in viva Sialic acid with C9 arm was also could be conjugated to TNFα. The carbohydrate conjugated TNFα exhibited reduced toxicity to mouse but enhanced anti-tumor activity to tumor in mice. Less

IL-1在宿主反应中起重要作用，包括免疫学、炎症和血液学反应，以及在细胞增殖和分化的调节中。因此，阐明EL-1的作用、产生及其调控机制具有重要意义。在这项研究中，我们研究了IL-1的作用及其调节机制的许多方面。1）IL-1信号转导。我们分析了IL-1作用导致A375人黑色素瘤细胞增殖抑制的机制。我们在CHOP基因下游发现了一个受p38 MAPK调控的新蛋白TRB 3。通过对TRB 3基因启动子区的分析，发现CHOP-ATP区对TRB 3基因的激活起重要作用。TRB 3还能抑制CHOP. 2）IL-1受体家族的转录活性。Toll样受体，IL-1家族，已知是细菌和合成寡核苷酸的信号分子。我们发现IL-1可增强小鼠肝细胞TLR 2的表达和基因激活， ...更多信息 母细胞TGFR通过下调IL-1诱导的IL-1受体I型（IL-1 RI）的上调而下调IL-1诱导的TLR 2表达。TGFβ还可抑制IL-1诱导的人成纤维细胞IL-1 RI的表达。3）IL-1α的基因表达机制：A375 R8细胞组成性产生IL-1α。我们发现IL-1α基因启动子的GC富集区对于组成型基因的激活是重要的。此外，Sp1与GC富集区的结合以及Sp1与HDAC 1的缔合对于IL-1α基因的激活是重要的。雌激素通过雌激素受体α激活人类风湿关节炎滑膜细胞中IL-1α启动子活性。4）糖结合IL-1：将唾液酸或唾液酸半乳糖与人IL-1α结合。糖结合的IL-1α的体外活性通常表现出其体外生物活性的降低。糖结合的IL-1α在体内表现出选择性活性，C9臂的唾液酸也可与TNFα结合。碳水化合物结合TNFα对小鼠的毒性降低，但对小鼠肿瘤的抗肿瘤活性增强。少

项目成果

Polyaromatic hydrocarbon increases mRNA level for interleukin 1 beta in human fibroblast-like synoviocyte line via aryl hydrocarbon receptor

多芳烃通过芳基烃受体增加人成纤维样滑膜细胞系中白细胞介素 1β 的 mRNA 水平

• 发表时间: 2004
• 期刊: Biol. Pharm. Bull. 27(3)
• 作者: Ayako Tyamaki;Hidetoshi Hayashi;Hironori Nakajima;Takemasa Takii;Daichi Katagiri;Keiji Miyzazawa;Kunitaka Hirose;Kikuo Onozaki
• 通讯作者: Kikuo Onozaki

Takii, T., Kawashima, S., Chiba, T., Hayashi, H., Hayashi, M., Hiroma, H., Kimura, H., Inukai, Y., Shibata, Y., Nagatsu, A., Sakakibara, J., Oomoto, Y., Hirose, K., Onozaki, K.: "Multiple mechanisms involved in the inhibition of proinflammatory cytokine p

泷井 T.、川岛 S.、千叶 T.、林 H.、林 M.、广间 H.、木村 H.、犬凯 Y.、柴田 Y.、长津 A.、

TGFβ down-regulates IL- Iα-induced functional TLR2 expression in murine hepatocytes

TGFβ下调小鼠肝细胞中IL-Iα诱导的功能性TLR2表达

• 发表时间: 2004
• 期刊: J. Leuk. Biol. 75(6)
• 作者: Takayuki Matsumura;Hidetoshi Hayashi;Takemasa Takii;Caroline F Thorn;Alexander S. Whitehead;Jun-ichiro Inoue;Kikuo Onozaki
• 通讯作者: Kikuo Onozaki

A.Tyamaki, H.Hayashi, H.Nakajima, T.Takii, D.Katagiri, K.Miyazawa, K.Hirose, K.Onozaki: "Polyaromatic hydrocarbon increases mRNA level for interleukin 1 beta in human fibroblast-like synoviocyte line via aryl hydrocarbon receptor"Biol.Pharm.Bull.. 27(3).

A.Tyamaki、H.Hayashi、H.Nakajima、T.Takii、D.Katagiri、K.Miyazawa、K.Hirose、K.Onozaki：“多芳烃可通过以下途径增加人成纤维细胞样滑膜细胞系中白细胞介素 1 β 的 mRNA 水平：

Matsumura T., Degawa, T., Takii, T., Hayashi, H., Okamoto, T., Inoue, J., Onozaki, K.: "TRAF6-NF-kB Pathway is Essential for IL-1-induced TLR2 Expression and Its Functional Response to TLR2 Ligand in Murine Hepatocytes"Immunology. (In press). (2003)

Matsumura T.、Dekawa, T.、Takii, T.、Hayashi, H.、Okamoto, T.、Inoue, J.、Onozaki, K.：“TRAF6-NF-kB 通路对于 IL-1 诱导的 TLR2 至关重要