Development of Kupffer cell targeting type-I interferon for the treatment of hepatitis via inducing anti-inflammatory and immunomodulatory actions.
Development of Kupffer cell targeting type-I interferon for the treatment of hepatitis via inducing anti-inflammatory and immunomodulatory actions.
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DOI：
10.1080/10717544.2018.1464083
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发表时间：
2018-11
期刊：
影响因子：
6
通讯作者：
Maruyama T
中科院分区：
文献类型：
--
作者：
Minayoshi Y;Maeda H;Yanagisawa H;Hamasaki K;Mizuta Y;Nishida K;Kinoshita R;Enoki Y;Imafuku T;Chuang VTG;Koga T;Fujiwara Y;Takeya M;Sonoda K;Wakayama T;Taguchi K;Ishima Y;Ishida T;Iwakiri Y;Tanaka M;Sasaki Y;Watanabe H;Otagiri M;Maruyama T
由于其多方面的抗炎和免疫调节作用，将I型干扰素递送至枯否细胞有可能成为治疗各种类型肝炎的一种新型疗法。在此我们报道了一种靶向枯否细胞的I型干扰素的制备，这是一种白蛋白 - IFNα2b融合蛋白，它包含高度甘露糖基化的N - 连接寡糖链，即Man - HSA(D494N) - IFNα2b，是通过结合白蛋白融合技术和定点诱变连接而成的。这种独特寡糖的存在使该蛋白能够高效、快速且优先地分布到枯否细胞中。与IFNα2b一样，Man - HSA(D494N) - IFNα2b可显著诱导RAW264.7细胞和小鼠分离的枯否细胞中IL - 10、IL - 1Ra、PD - L1的mRNA水平升高，并且通过阻断干扰素受体可在很大程度上抑制这些诱导作用。这些数据表明Man - HSA(D494N) - IFNα2b保留了I型干扰素的生物学活性。Man - HSA(D494N) - IFNα2b在刀豆蛋白A（Con - A）诱导的肝炎模型小鼠中显著抑制了肝损伤，从而提高了它们的存活率。此外，在Con - A攻击后2小时给予Man - HSA(D494N) - IFNα2b也具有肝脏保护作用。总之，这项概念验证研究通过其抗炎和免疫调节作用证明了靶向枯否细胞的I型干扰素对肝炎的治疗效果和实用性。
Because of its multifaceted anti-inflammatory and immunomodulatory effects, delivering type-I interferon to Kupffer cells has the potential to function as a novel type of therapy for the treatment of various types of hepatitis. We report herein on the preparation of a Kupffer cell targeting type-I interferon, an albumin-IFNα2b fusion protein that contains highly mannosylated N-linked oligosaccharide chains, Man-HSA(D494N)-IFNα2b, attached by combining albumin fusion technology and site-directed mutagenesis. The presence of this unique oligosaccharide permits the protein to be efficiently, rapidly and preferentially distributed to Kupffer cells. Likewise IFNα2b, Man-HSA(D494N)-IFNα2b caused a significant induction in the mRNA levels of IL-10, IL-1Ra, PD-L1 in RAW264.7 cells and mouse isolated Kupffer cells, and these inductions were largely inhibited by blocking the interferon receptor. These data indicate that Man-HSA(D494N)-IFNα2b retained the biological activities of type-I interferon. Man-HSA(D494N)-IFNα2b significantly inhibited liver injury in Concanavalin A (Con-A)-induced hepatitis model mice, and consequently improved their survival rate. Moreover, the post-administration of Man-HSA(D494N)-IFNα2b at 2 h after the Con-A challenge also exerted hepato-protective effects. In conclusion, this proof-of-concept study demonstrates the therapeutic effectiveness and utility of Kupffer cell targeting type-I interferon against hepatitis via its anti-inflammatory and immunomodulatory actions.
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