Department of Pathology, Dalhousie University, Tupper Building, 5850 College Street, Halifax, Nova Scotia B3H 4R2, Canada.
Department of Microbiology & Immunology, Dalhousie University, Tupper Building, 5850 College Street, Halifax, Nova Scotia B3H 4R2, Canada.
Biochem Biophys Res Commun. 2014 Jan 10;443(2):524-30. doi: 10.1016/j.bbrc.2013.11.119. Epub 2013 Dec 6.
Surfen (bis-2-methyl-4-amino-quinolyl-6-carbamide) binds to glycosaminoglycans (GAGs) and has been shown to influence their function, and the function of proteoglycans (complexes of GAGs linked to a core protein). T cells synthesize, secrete and express GAGs and proteoglycans which are involved in several aspects of T cell function. However, there are as yet no studies on the effect of GAG-binding agents such as surfen on T cell function. In this study, surfen was found to influence murine T cell activation. Doses between 2.5 and 20 μM produced a graduated reduction in the proliferation of T cells activated with anti-CD3/CD28 antibody-coated T cell expander beads. Surfen (20 mg/kg) was also administered to mice treated with anti-CD3 antibody to activate T cells in vivo. Lymphocytes from surfen-treated mice also showed reduced proliferation and lymph node cell counts were reduced. Surfen reduced labeling with a cell viability marker (7-ADD) but to a much lower extent than its effect on proliferation. Surfen also reduced CD25 (the α-subunit of the interleukin (IL)-2 receptor) expression with no effect on CD69 expression in T cells treated in vivo but not in vitro. When receptor activation was bypassed by treating T cells in vitro with phorbyl myristate acetate (10 ng/ml) and ionomycin (100 ng/ml), surfen treatment either increased proliferation (10 μM) or had no effect (2.5, 5 and 20 μM). In vitro treatment of T cells with surfen had no effect on IL-2 or interferon-γ synthesis and did not alter proliferation of the IL-2 dependent cell line CTLL-2. The effect of surfen was antagonized dose-dependently by co-treatment with heparin sulfate. We conclude that surfen inhibits T cell proliferation in vitro and in vivo. When T cell receptor-driven activation is bypassed surfen had a neutral or stimulatory effect on T cell proliferation. The results imply that endogenous GAGs and proteoglycans play a complex role in promoting or inhibiting different aspects of T cell activation.
（双-2-甲基-4-氨基-喹啉-6-甲酰胺）与糖胺聚糖（GAGs）结合，并已被证明影响其功能，以及糖蛋白（与核心蛋白相连的 GAG 复合物）的功能。T 细胞合成、分泌和表达 GAGs 和糖蛋白，这些物质参与 T 细胞功能的几个方面。然而，目前还没有研究 GAG 结合剂（如沙芬）对 T 细胞功能的影响。在这项研究中，发现沙芬影响了小鼠 T 细胞的激活。在 2.5 和 20 μM 之间的剂量产生了对用抗-CD3/CD28 抗体包被的 T 细胞扩展珠激活的 T 细胞增殖的逐渐减少。沙芬（20mg/kg）也被给予用抗-CD3 抗体处理的小鼠，以在体内激活 T 细胞。来自沙芬处理的小鼠的淋巴细胞也显示出增殖减少，并且淋巴结细胞计数减少。沙芬减少了细胞活力标记物（7-ADD）的标记，但与对增殖的影响相比，程度要低得多。沙芬还降低了体内处理的 T 细胞中 CD25（白细胞介素（IL）-2 受体的 α 亚单位）的表达，但对体外处理的 T 细胞中 CD69 的表达没有影响。当通过用佛波醇肉豆蔻酸酯（10ng/ml）和离子霉素（100ng/ml）体外处理 T 细胞绕过受体激活时，沙芬处理要么增加增殖（10μM），要么没有影响（2.5、5 和 20μM）。体外处理 T 细胞的沙芬对 IL-2 或干扰素-γ的合成没有影响，也没有改变 IL-2 依赖性细胞系 CTLL-2 的增殖。肝素硫酸盐的共同处理剂量依赖性地拮抗沙芬的作用。我们得出结论，沙芬抑制体内和体外 T 细胞增殖。当 T 细胞受体驱动的激活被绕过时，沙芬对 T 细胞增殖具有中性或刺激作用。结果表明，内源性 GAGs 和糖蛋白在促进或抑制 T 细胞激活的不同方面发挥着复杂的作用。
