FUNCTION OF THE SELECTIN FAMILY AND FUNDAMENTAL STUDY ON THE DEVELOPMENT OF A NEW DRUGS FOR ANTI-INFLAMMATION AND ANTI-TUMOUR MATASTASIS

在1995-1996年的项目中，我们发现了新的选择素配体、硫酸化糖链（如硫苷脂）和几种硫酸化寡糖（硫酸化甲壳素、硫酸化透明质酸等）。硫苷脂是从脑中分离的一种半乳糖神经酰胺，是L-和P-选择素的潜在配体，它特异性结合L-和P-选择素，但不结合E-选择素。二价阳离子是不必要的硫苷脂的L-和P-选择素的结合。这些性质不同于已被鉴定为L-、P-和E-选择素的共同配体的SLex。我们发现，硫苷脂强烈阻断眼镜蛇毒因子诱导的肺损伤，这被确定为L-和P-依赖性肺部炎症。硫脂还阻断由输尿管梗阻后的肾小管损伤诱导的单核细胞浸润到肾间质中，这被鉴定为L-选择素依赖性肾脏炎症之一。硫苷脂还阻断了B-16黑色素瘤细胞的肺转移。硫苷脂选择性地在B细胞上表达，而在T细胞上不表达，并且抑制B细胞增殖和IG产生。这些结果表明，L-选择素及其配体系统在启动B细胞活化和抗体产生中具有新的作用，本项目的研究结果可能为开发抗感染和抗肿瘤细胞转移的新药提供潜在的应用。

In this project years (1995-1996), we found new selectin ligands, sulfated sugar chains, such as sulfatide, and several kinds of sulfated oligosaccharides (sulfated chitin, sulfated hyaluronic acid, etc.). Sulfatide, isolated from brain, a sulfated galactosylc eramide is a potential ligand for L- and P-selectins, which binds specifically L- and P-selectins but not to E-selectin. Divalent cations were not necessary for the binding of sulfatide to L- and P-selectins. These properties are different from SLex which has been identified as a common ligand for L-, P-, and E-selectins. We found that the sulfatide blocks strongly cobra venom factor-induced lung injury which is identified as an L- and P-dependent lung inflammation. Sulfatide also blocked mononuclear cell infiltration into the kidney interstitium induced by tublar injury following ureteral obstruction, which is identified as one of the L-selectin-dependent kidney inflammation. Sulfatide also blocked the lung metastasis of the B-16 melanoma cells. Sulfatide was selectively expressed on B cells, but not on T cells, and also inhibited the B cell proliferation and Ig production. These results suggested a novel role of the L-selectin/its ligand system in the initiation of B cell activation and antibody production.The results obtained in the project years may potentially be applied for the development of a new drugs for the anti-infmammation and anti-tumor cell metastasis.