Analysis of CD29/VLA integrin in T cell immune regulation and its clinical significance

CD29/VLA整合素在T细胞免疫调节中的作用分析及其临床意义

• 批准号: 11307009
• 负责人: MORIMOTO Chikao
• 金额: $ 23.42万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A).
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11307009/
• 关键词: B cell progenitors cells; integrin α5β1; Extracelluar signal-regulated kinase; p27(Kip1); cyclin-dependent kinase; BM stromal cells; p27^<ldpl>; CD29; VLA; インテグリン; Cas-L分子; T細胞共刺激; T細胞遊走; チロシンリン酸化

Attachment to bone marrow(BM)stromal cells is crucial for the normal growth and development of B-cell progenitors(pro-B). However, the molecular mechanisms by which contact facilitates the proliferation of pro-B cells are not completely understood. This study was performed to investigate this interaction.Attachment to both KM102 and normal BM stromal cells significantly promoted the growth of Reh cells. Pretreatment of Reh cells with anti-integrin beta1 or alpha5 monoclonal antibody(mAb), but not alpha4 or ICAM-1 mAb, abrogated this enhancement of proliferation. Furthermore, stroma attachment resulted in shortening of the G(1)phase of cell cycle, significant increases cdk2 activity, degradation of cdk inhibitor p27-GST protein, and decrease in levels of p27(Kip1)protein. In addition, solid-phase cross-linking of alpha5 via immobilized antibody also resulted in extracellular signal-regulated(ERK)-2 kinase phosphorylation, increase in cdk2 activity, decrease in levels of p27(Kip1)protein, and enhanced proliferation that was inhibited by treatment with PD98059, a specific ERK inhibitor.Integrin alpha5beta1-mediated stroma contact promotes the proliferation of B-cell progenitors through the activation of ERK-2, which in tum modulates cell cycle regulation machinery including induction of cdk2 activity and degradation of p27(Kip1)and contributing to acceleration of the G(1)phase of cell cycle progression.

骨髓基质细胞的附着对b细胞祖细胞（pro-B）的正常生长发育至关重要。然而，接触促进前b细胞增殖的分子机制尚不完全清楚。本研究旨在调查这种相互作用。KM102和正常骨髓基质细胞均能显著促进Reh细胞的生长。用抗整合素β 1或α 5单克隆抗体（mAb）预处理Reh细胞，而不使用α 4或ICAM-1单克隆抗体，可消除这种增殖增强。此外，基质附着导致细胞周期G(1)期缩短，cdk2活性显著升高，cdk抑制剂p27- gst蛋白降解，p27（Kip1）蛋白水平降低。此外，通过固定抗体将alpha5固相交联还导致细胞外信号调节(ERK)-2激酶磷酸化，cdk2活性增加，p27（Kip1）蛋白水平降低，并通过PD98059（一种特异性ERK抑制剂）抑制增殖。整合素α 5β 1介导的基质接触通过激活ERK-2促进b细胞祖细胞的增殖，ERK-2反过来调节细胞周期调节机制，包括诱导cdk2活性和p27（Kip1）的降解，并有助于加速细胞周期的G(1)期进程。

项目成果

Qing Y-W,Kitagawa M,Higashi M,Ishii G,Morimoto C,Harigaya K: "Activation of mitogen-activated protein kinas through α5β1 integrin is required for the cell cycle progression of B progenita cell line, Reh, on human marrow stromal cells"Exp.Hematol. 28. 1147

Qing Y-W、Kitakawa M、Higashi M、Ishii G、Morimoto C、Harigaya K：“人骨髓基质细胞上的 B 祖细胞系 Reh 的细胞周期进展需要通过 α5β1 整合素激活有丝分裂原激活蛋白激酶”实验。 28. 1147

Iwata S,Ohashi Y,Kamiguchi K,Morimoto C: "Beta 1-integrin-mediated cell signaling in T lymphocytes"J Dermatol Sci. 23. 75-86 (2000)

Iwata S、Ohashi Y、Kamiguchi K、Morimoto C：“T 淋巴细胞中 Beta 1-整合素介导的细胞信号传导”J Dermatol Sci。

Munakata Y, Iwata S, Dobers J, Ishii T, Nori M, Tanaka H, Morimoto C: "Novel in Vitro effects of bucillamine : Inhibitory iffects on proinflammatory cytokine production and tranendothelial migration of T Cell."Arthr.and Rheum. 43. 1616-1623 (2000)

Munakata Y、Iwata S、Dobers J、Ishii T、Nori M、Tanaka H、Morimoto C：“布西拉明的新型体外作用：对促炎细胞因子产生和 T 细胞跨内皮迁移的抑制作用。”Arthr. 和 Rheum。

Ikushima H, Munakata Y, Ishii T, Iwata S, Terashima M, Tanaka H, Schlossman SF, Morimoto C.: "Internalization of CD26 by mannose 6-phosphate/insulin-like growth factor II receptor contributes to T cell activation"Proc.Natl.Acad.Sci.. 97. 8439-8444 (2000)

Ikushima H、Munakata Y、Ishii T、Iwata S、Terashima M、Tanaka H、Schlossman SF、Morimoto C.：“6-磷酸甘露糖/胰岛素样生长因子 II 受体对 CD26 的内化有助于 T 细胞激活”Proc。

Homma T, Hosono O, Iwata S, Ando S, Sasaki K, Nishi T, Kawasaki H, Tanaka H, Morimoto C.: "Recognition of cell surface GD3 by monoclonal antibody anti-6C2 in rheumatoid arthiritis synovial fluid"Arthr.& Rheum.. (In press).

Homma T、Hosono O、Iwata S、Ando S、Sasaki K、Nishi T、Kawasaki H、Tanaka H、Morimoto C.：“类风湿关节炎滑液中抗 6C2 单克隆抗体对细胞表面 GD3 的识别”Arthr。