Development of therapeutics using interleukin-4 (IL-4) mutein in atherosclerotic mouse model showing Th1-dominant immune response

对动脉粥样硬化的炎症过程及其治疗意义进行了研究。溶血磷脂酸(LPA)可诱导NADPH依赖的细胞内氧化应激、RAC-1(Small GTP Ase)激活和MCP-1的表达，该通路可被抗氧化剂和他汀类药物抑制。这样的体外实验表明血管细胞具有炎性表型。在载脂蛋白E基因敲除小鼠中给予可溶性的INF&γ&gt；受体可抑制动脉粥样硬化的形成。此外，STAT6基因敲除小鼠(B6主干)不仅表现出免疫应答中的Th1改变，而且还表现出肥胖和糖耐量的表型，提示炎症、免疫过程与动脉粥样硬化或代谢危险因素密切相关。将野生型小鼠IL-4基因及其细胞特异性突变体Q116E亚克隆入腺病毒衍生表达载体。原代培养的小鼠血管细胞检测炎症表型的变化。复制缺陷型腺病毒载体的研制正试图用于体内实验。这些结果进一步强调了动脉粥样硬化炎症过程的重要性，并提示了治疗的意义。我们感谢您对我们工作的支持，并将继续尽最大努力解决人类心血管疾病的病理问题。

Inflammatory process of atherosclerosis and its therapeutic implication have been studied. LPA (Lysophosphatidic acid) showed mitogenic activity in the cultured smooth muscle cells as well as induction of NADPH-dependent intracellular oxidative stress, rac-1 (small GTPase) activation, and MCP-1 expression, of which pathway was inhibited by antioxidant and statin. Such in vitro experiments suggested an inflammatory phenotype of vascular cells. Administration of soluble INF_<-γ> receptor in ApoE knockout mice resulted in the suppression of atherogenesis. Moreover, STAT6 knockout mice (B6 backbone) showed not only Th1 shift in the immunological response but the phenotypes of obesity and glucose tolerance, suggesting a close relationship between inflammatory, immunological process and atherosclerosis or metabolic risk factors. Wild type mouse IL-4 gene and its specific cell oriented mutein, Q116E, were sub-cloned into adenovirus-derive expression (shuttle) vector. Primary mouse vascular cells were tested for the changes in inflammatory phenotypes. Development of replication-deficient adenoviral vector was attempting for in vivo experiments. These results further highlighted the importance of inflammatory process of atherosclerosis and suggest the therapeutic implications. We gratefully appreciate for supporting our work and continue to make our best effort to dissolve the pathological problems in human cardiovascular diseases.