Basic study concerning the gene therapy using p53 gene toward rheumatoid arthritis

p53基因治疗类风湿性关节炎的基础研究

• 批准号: 14570419
• 负责人: MIGITA Kiyoshi
• 金额: $ 2.11万
• 依托单位: NHO Nagasaki Medical Center
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 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-14570419/
• 关键词: Rheumatoid arthritis; Mitogen-activated protein kinase; p53; leflunomide; matrixmetalloproteincese; tacrolimus; 細胞周期; プロテアゾーム

Leflunomide is an immuneregulatory drug that has shown effectiveness in the prevention of organ graft rejection as well as in an array of autoimmune diseases. In order to explore the mechanism of leflunomide-mediated immunosuppression, we investigated the effects of leflunomide on antigen-stimulated T cells in vivo. Leflunomide induced p53 expression in SEB-activated V□8^+ T cells. Also, increased levels of proliferating cell nuclear antigen (PCNA) and Cyclin E expression of SEB-activated V□8^+ T cells was suppressed by leflunomide. Our data suggest that the leflunomide-mediated cell cycle regulation of activated T cells may present a potential mechanism of immunosuppression achieved by leflunomide treatment. We also investigated the effects of A77 1726, leflunomide's active metabolite, on mitogen-activated protein kinases (MAPK) activation in IL-1β-stimulated rheumatoid synovial fibroblasts. The effects of A77 1726 on the secretion of matrix metalloproteinases (MMPs) from rheumatoid synovial fibroblasts were also examined. A77 1726 partially A77 1726 efficiently suppressed IL-1β-stimulated rheumatoid synovial fibroblasts. Our results suggest that the suppression of MAPK signaling pathway and MMPs synthesis in rheumatoid synovial fibroblats is a possible mechanism for the inhibitory activity of leflunomide against rheumatoid arthritis.

来氟米特是一种免疫调节药物，在预防器官移植排斥反应和一系列自身免疫性疾病方面表现出有效性。为了探讨来氟米特介导的免疫抑制机制，我们在体内研究了来氟米特对抗原刺激的T细胞的影响。来氟米特诱导SEB激活的V□8^+ T细胞中的p53表达。此外，来氟米特还抑制了SEB激活的V□8^+ T细胞的增殖细胞核抗原（PCNA）和细胞周期蛋白E表达水平的增加。我们的数据表明，来氟米特介导的活化T细胞的细胞周期调节可能是来氟米特治疗实现免疫抑制的潜在机制。我们还研究了A77 1726（来氟米特的活性代谢产物）对IL-1β刺激的类风湿滑膜成纤维细胞中丝裂原活化蛋白激酶（MAPK）活化的影响。还检测了A77 1726对类风湿性滑膜成纤维细胞分泌基质金属蛋白酶（MMPs）的影响。A77 1726部分抑制IL-1β刺激的类风湿性滑膜成纤维细胞。我们的研究结果表明，MAPK信号通路的抑制和MMPs的合成在类风湿性滑膜成纤维细胞是一个可能的机制来氟米特对类风湿性关节炎的抑制活性。

项目成果

Yamasaki S, Nakashima T, Kawakami A, Miyashita T, Tanaka F, Ida H, Migita K, Origuchi T, Eguchi K: "Cytokines regulate fibroblast-like synovial cell differentiation to adipocyte-like cells."Rheumatology. 43. 448-452 (2004)

Yamasaki S、Nakashima T、Kawakami A、Miyashita T、Tanaka F、Ida H、Migita K、Origuchi T、Eguchi K：“细胞因子调节成纤维细胞样滑膜细胞向脂肪细胞样细胞的分化。”风湿病学。

Tanaka F, Migita K, Kawabe Y, Aoyagi T, Ida H, Kawakami A, Eguchi K.: "Interleukin-18 induces serum amyloid A (SAA) protein production from rheumatoid synovial fibroblasts"Life Sci. 74. 1671-1679 (2004)

Tanaka F、Migita K、Kawabe Y、Aoyagi T、Ida H、Kawakami A、Eguchi K.：“Interleukin-18 诱导类风湿滑膜成纤维细胞产生血清淀粉样蛋白 A (SAA)”《生命科学》。

Origuchi T, Kawakami A, Ide H, Kamachi M, Tanaka F, Ida H, Kawakami A, Migita K, Eguchi K: "Corrlation between interleukin 10 gene promoter region polymorphisms and clinical manifestations in Jamanese patients with Sjogren's syndrome."Ann Rheum Dis. 62. 1

Origuchi T、Kawakami A、Ide H、Kamachi M、Tanaka F、Ida H、Kawakami A、Migita K、Eguchi K：“白细胞介素 10 基因启动子区域多态性与日本干燥综合征患者临床表现的相关性。”Ann Rheum Dis

Ida H, Nakashima T, Kedersha NL, Yamasaki S, Huang M, Izumi Y, Miyashita T, Origuchi T, Kawakami A, Migita K, Bird PI, Anderson P, Eguchi K: "Granzyme B leakage-induced cell death : a new type of activation-induced natural killer cell death."Eur J Immunol

Ida H、Nakashima T、Kedersha NL、Yamasaki S、Huang M、Izumi Y、Miyashita T、Origuchi T、Kawakami A、Migita K、Bird PI、Anderson P、Eguchi K：“颗粒酶 B 渗漏诱导的细胞死亡：一种新的方法”

Ichinose K, Migita K, Sekita T, Hamada H, Ezaki H, Mukoubara S, Eguchi K: "Parvovirus B19 infection and myofasciitis."Clin Rheumatol. 23. 184-185 (2004)

Ichinose K、Migita K、Sekita T、Hamada H、Ezaki H、Mukoubara S、Eguchi K：“细小病毒 B19 感染和肌筋膜炎。”Clin Rheumatol。