Nakajima Akira, Ibi Daisuke, Nagai Taku, Yamada Shinnosuke, Nabeshima Toshitaka, Yamada Kiyofumi
Department of Neuropsychopharmacology and Hospital Pharmacy, Graduate School of Medicine, Nagoya University, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8560, Japan.
Department of Neuropsychopharmacology and Hospital Pharmacy, Graduate School of Medicine, Nagoya University, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8560, Japan; Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Yagotoyama, Tenpaku-ku, Nagoya 468-8503, Japan.
Eur J Pharmacol. 2014 Dec 15;745:166-75. doi: 10.1016/j.ejphar.2014.08.034. Epub 2014 Sep 10.
Astrocytes are important modulators of the immune and inflammatory reactions in the central nervous system. We have recently demonstrated the role of interferon-induced transmembrane protein 3 (IFITM3) in long-lasting neuronal impairments in mice following neonatal immune challenge by injections of the double-stranded RNA analog polyriboinosinic polyribocytidylic acid. Here, we show that IFITM3 is induced after lipopolysaccharide (LPS) treatment in cultured astrocytes. The induction of IFITM3 by LPS was completely suppressed by the addition of anti-interferon-β (IFN-β) antibody. In addition, neutralization of tumor necrosis factor-α (TNF-α) with its antibody partially inhibited the induction of IFITM3, suggesting that LPS induces IFITM3 through autocrine secretion of IFN-β and TNF-α. Furthermore, experiments using pharmacological inhibitors suggest that LPS induces IFITM3 through activation of TANK-binding kinase 1, p38 mitogen-activated protein kinase, and nuclear factor-κB pathways. Together, these findings may provide new insight into the role of IFITM3 in the pathogenesis of neurodevelopmental diseases associated with immune activation.
星形胶质细胞是中枢神经系统免疫和炎症反应的重要调节因子。我们最近证明了干扰素诱导跨膜蛋白3（IFITM3）在新生小鼠经注射双链RNA类似物聚肌苷酸-聚胞苷酸进行免疫攻击后导致的长期神经元损伤中的作用。在此，我们表明在培养的星形胶质细胞中，脂多糖（LPS）处理后IFITM3被诱导。添加抗干扰素-β（IFN-β）抗体可完全抑制LPS对IFITM3的诱导。此外，用肿瘤坏死因子-α（TNF-α）抗体中和可部分抑制IFITM3的诱导，这表明LPS通过IFN-β和TNF-α的自分泌来诱导IFITM3。此外，使用药理学抑制剂的实验表明，LPS通过激活TANK结合激酶1、p38丝裂原活化蛋白激酶和核因子-κB途径来诱导IFITM3。总之，这些发现可能为IFITM3在与免疫激活相关的神经发育疾病发病机制中的作用提供新的见解。
