Analysis of interaction of CD40 and CD40-ligand in autoimmune diseases and research for regulation drugs.

自身免疫性疾病中CD40与CD40配体相互作用分析及调控药物研究。

• 批准号: 14370168
• 负责人: KATO Kazunori
• 金额: $ 6.53万
• 依托单位: Sapporo Medical 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 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370168/
• 关键词: CD40-ligand; mRNA stability; Soluble factor; Column for plasma exchange; Thalidomide; サリドマイド誘導体; MMP阻害剤; 川崎病; 血管新生因子; サリドマイド誘導

The expression of CD154(CD40-ligand) on activated CD4-positive T cells is known to be transient and tightly regulated for antigen-specific immune responses, and is increase, and prolonged among patients with systemic lupus erythematosus(SLE). We investigated the regulation of CD154 expression by determining the protein and mRNA expression with PMA and ionomycin stimulation in CD4-positive T cells, and confirmed their increase and prolongation in SLE T cells. Treatment with actinomycin D, a transcription inhibitor, after PMA and ionomycin stimulation was performed, and the findings revealed that the stability of CD154 mRNA increased significantly in activated SLE T cells compared with that of controls. However, alternations or abnormal sequences were not identified in the 3' untranslated region(3'UTR), including AU-rich elements and CU-rich sequences, while their partial involvement in the post-transcriptional regulation of CD154 mRNA stability has been reported. With 96h culture in vitro, the destabilization of CD154 mRNA was demonstrated, resulting in a corresponding decrease and normalization of surface expression on activated SLE T cells. We suggest that the CD154 expression on T cells from SLE patients may be increased and prolonged, with mRNA stabilization being related to a continuous stimulation in vivo.

已知活化的CD 4阳性T细胞上的CD 154（CD 40-配体）的表达对于抗原特异性免疫应答是短暂的和严格调节的，并且在系统性红斑狼疮（SLE）患者中增加和延长。我们通过测定PMA和离子霉素刺激CD 4阳性T细胞中的蛋白质和mRNA表达来研究CD 154表达的调节，并证实了它们在SLE T细胞中的增加和延长。在PMA和离子霉素刺激后，用转录抑制剂放线菌素D处理，结果显示，与对照组相比，活化的SLE T细胞中CD 154 mRNA的稳定性显著增加。然而，在3'非翻译区（3' UTR）中没有发现改变或异常序列，包括富含AU的元件和富含CU的序列，而它们部分参与了CD 154 mRNA稳定性的转录后调节。体外培养96 h后，CD 154 mRNA的失稳，导致活化的SLE T细胞表面表达相应减少和正常化。我们认为，从SLE患者的T细胞上的CD 154表达可能增加和延长，mRNA稳定与体内的连续刺激。

项目成果

Kuronuma, K., et al.: "Pulmonary surfactant protein A augments the phagocytosis of Streptococcus pneumoniae by alveolar macrophages through a casein kinase 2-dependent increase of cell surface localization of scavenger receptor A."J.Biol.Chem.. (In press)

Kuronuma, K. 等人：“肺表面活性蛋白 A 通过酪蛋白激酶 2 依赖性增加清道夫受体 A 的细胞表面定位，增强肺泡巨噬细胞对肺炎链球菌的吞噬作用。”J.Biol.Chem..（In

Kato, K., et al.: "U5A2-13,an antigen originally found on mouse NK-T cells, is an early inducible cell surface antigen during lymphoid activation."Cellular Immunology. 221. 27-36 (2003)

Kato, K. 等人：“U5A2-13 是一种最初在小鼠 NK-T 细胞上发现的抗原，是淋巴激活过程中的早期可诱导细胞表面抗原。”细胞免疫学。

Kato, K., Ikarashi, Y., Sugahara, T., Yasumoto, A., Sancho, D., Yoshida, M., Takaue, Y., Kobayashi, Y., Sanchez-Madrid, F., Wakasugi, H.: "U5A2-13, an antigen originally found on mouse NK-like T cells, is an early inducible cell surface antigen during lym

加藤，K.，五十岚，Y.，菅原，T.，安本，A.，桑乔，D.，吉田，M.，高上，Y.，小林，Y.，桑切斯-马德里，F.，若杉，H

K.Kato, et al.: "T cell conditioned medium efficiently induces the maturation and function of human dendritic cells"J. Leukocyte Biol.. 70. 941-949 (2001)

K.Kato 等人：“T 细胞条件培养基有效诱导人树突状细胞的成熟和功能”J.

Kuronuma, K., et al.: "Pulmonary surfactant protein A augments the phagocytosis of streptococcus pneumoniae by alveloar macrophage・・・・"Journal of Biological Chemistry. (In press). (2004)

Kuronuma, K. 等人：“肺表面活性蛋白 A 增强肺泡巨噬细胞对肺炎链球菌的吞噬作用……”生物化学杂志（2004 年出版）。