The mechanism and its regulation of interleukin 1 biological activities

白细胞介素1生物活性的机制及其调控

• 批准号: 11470487
• 负责人: ONOZAKI Kikuo
• 金额: $ 6.27万
• 依托单位: Faculty of Pharmaceutical Sciences, 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: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470487/
• 关键词: IL-1; IL-1 receptor; cytokine; ODC; antizyme; CHOP; melanoma; TLR

IL-1 plays an important role in host reactions, including immunologic, inflammatory and hematologic reactions, and in regulation of cell proliferation and differentiation. In this study we attempted to clarify (A) the mechanism of IL-1 signaling leading to the inhibition of cell proliferation of human melanoma cells A375, (B) the regulatory mechanism of expression of IL-1 receptor (IL-1R) and its family in vitro and in vivo. The following points have been clarified.(A)1) It was suggested that IL-1 up-regulated the protein level of AZ, a reguratory factor of ornithine decarboxylase (ODC), at translational level, and IL-1 responsive region was present within the sequence of AZ mRNA.2) CHOP contributed to the antiproliferative effect of IL-1 by augmenting IL-6 transcription3) CHOP augmented the transcriptional activity of many factors, including NF-IL-6, AP-1, ISRE and NF-κB.4) CHOP also appeared to stabilize the protein levels of other C/EBP family members.5) TNF inhibited the proliferation of both IL-1 sensitive A375-6 cells and IL-1 resistant A375-R8 cells. The p38MAPK-dependent antiproliferative pathway of TNF was observed in these two cell clones however p38MAPK-independent apoptosis pathway was observed in only R8 cells. The anti-apoptosis factor with very short half life appeared to be present in A375-6 cells but not in R8 cells.

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。本研究试图阐明（A）IL-1信号通路抑制人黑色素瘤细胞A375增殖的机制;（B）IL-1受体（IL-1 R）及其家族表达的调控机制。澄清了以下几点。(A)1)提示IL-1在翻译水平上调了ODC调节因子AZ的蛋白水平，AZ mRNA序列中存在IL-1反应区; 2）CHOP通过促进IL-6的转录而参与IL-1的抗增殖作用; 3）CHOP通过促进NF-IL-6、AP-1、NF-κ B 4）CHOP还可稳定C/EBP家族其他成员的蛋白水平。5）TNF可抑制IL-1敏感的A375-6细胞和IL-1抵抗的A375-R8细胞的增殖。在这两个细胞克隆中观察到TNF的p38 MAPK依赖性抗增殖途径，而仅在R8细胞中观察到p38 MAPK非依赖性凋亡途径。半衰期很短的抗凋亡因子似乎存在于A375-6细胞中，但不存在于R8细胞中。

项目成果

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T.Takii、C.Abe、A.Tamura、S.Ramayah、J.T.Belisle、P.J.Brennan、K.Onozaki：“白细胞介素 1 或肿瘤坏死因子 α 增强了分枝杆菌对人类成纤维细胞的细胞毒性作用：应用于评估M. 临床分离株

A.Ito,T.Takii,T.Matsumura,K.Onozaki: "Augmentation of type I IL-1 receptor expression and IL-1 signaling by IL-6 and glucocorticoid in murine hepatocytes"Journal of Immunology. 162・7. 4260-4265 (1999)

A.Ito、T.Takii、T.Matsumura、K.Onozaki：“小鼠肝细胞中 IL-6 和糖皮质激素增强 I 型 IL-1 受体表达和 IL-1 信号传导”《免疫学杂志》162・7。 -4265 (1999)

T.Takii,H.Honda,S.Sasayama,T.Kobayashi,H.Ikezawa,S.Udaka,Y.Oomoto,K.Onozaki: "Human interelukin-1 receptor antagonist: large-scale expression in Bacillus brevis 47-50"Journal of Inerferon and Cytokine Research. 19・11. (1999)

T. Takii、H. Honda、S. Sasayama、T. Kobayashi、H. Ikezawa、S. Udaka、Y. Oomoto、K. Onozaki：“人白细胞介素 1 受体拮抗剂：在短芽孢杆菌 47-50 中大规模表达“干扰素和细胞因子研究杂志。19・11。（1999）

T.Hattori, S.Itoh, H.Hayashi, T.Chiba, T.Takii, K.Yoshizaki, K.Onozaki: "CHOP, a basic leucine zipper transcriptional factor, contributes to the antiproliferative effect of IL-1 on human melanoma cells A375 through augmenting transcnption of IL-6"J. Inter

T.Hattori、S.Itoh、H.Hayashi、T.Chiba、T.Takii、K.Yoshizaki、K.Onozaki：“CHOP 是一种碱性亮氨酸拉链转录因子，有助于 IL-1 对人类黑色素瘤的抗增殖作用

K.Ono,T.Takii,K.Onozaki,M.Ikawa,M.Okabe,M.Sawada: "Migration of exogenous immature hematopoietic cells into adult mouse brain parenchyma under GFP-expressing bone marrow chimera"Biochemical and Biophysical Research Communications. 262・3. 610-614 (1999)

K. Ono、T. Takii、K. Onozaki、M. Ikawa、M. Okabe、M. Sawada：“在表达 GFP 的骨髓嵌合体下，外源未成熟造血细胞迁移到成年小鼠脑实质中”生物化学和生物物理研究通讯。 262・3。610-614（1999）