Okazaki Satoshi, Boku Shuken, Otsuka Ikuo, Horai Tadasu, Kimura Atsushi, Shimmyo Naofumi, Yamaki Naruhisa, Hishimoto Akitoyo
Department of Psychiatry, Kobe University Graduate School of Medicine, Kobe, Japan.
Department of Psychiatry, Kobe University Graduate School of Medicine, Kobe, Japan; Department of Neuropsychiatry, Kumamoto University Faculty of Life Sciences, Kumamoto, Japan.
J Psychiatr Res. 2021 Mar;135:237-242. doi: 10.1016/j.jpsychires.2021.01.033. Epub 2021 Jan 21.
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine and promotes neurogenesis and neuroprotection in brains. In addition, MIF has been identified as a potential marker of schizophrenia (SCZ). Our recent study also showed that serum MIF level is higher in SCZ and positively correlated with antipsychotic doses, and that MIF promoter polymorphisms are associated with SCZ. Here, we investigated the effects of antipsychotics such as clozapine on MIF expression in primary cultured astrocytes derived from neonatal mouse forebrain. MIF mRNA expression was estimated with quantitative reverse-transcription polymerase chain reaction. MIF protein concentration was measured with enzyme-linked immunosorbent assay. The histone acetylation of MIF promoter was examined with chromatin immunoprecipitation assay. As a result, common antipsychotics, especially clozapine, increased MIF mRNA expression in a dose-dependent manner. Clozapine increased MIF mRNA expression and protein concentration in a time-dependent manner. Moreover, clozapine increased the acetylation of histone H3 at lysine 27 residues (H3K27) in MIF promoter. In conclusion, we provide novel evidence that antipsychotics such as clozapine increases MIF expression via the acetylation of H3K27 in astrocytes, and that MIF may have a potential role for astrocytes in the action mechanisms of antipsychotics.
巨噬细胞移动抑制因子（MIF）是一种多效细胞因子，可促进大脑中的神经发生和神经保护作用。此外，MIF已被确定为精神分裂症（SCZ）的一个潜在标志物。我们最近的研究还表明，SCZ患者的血清MIF水平较高，且与抗精神病药物剂量呈正相关，并且MIF启动子多态性与SCZ有关。在此，我们研究了氯氮平之类的抗精神病药物对源自新生小鼠前脑的原代培养星形胶质细胞中MIF表达的影响。采用定量逆转录聚合酶链反应来评估MIF mRNA表达。用酶联免疫吸附测定法测量MIF蛋白浓度。用染色质免疫沉淀测定法检测MIF启动子的组蛋白乙酰化。结果显示，常用抗精神病药物，尤其是氯氮平，以剂量依赖性方式增加MIF mRNA表达。氯氮平以时间依赖性方式增加MIF mRNA表达和蛋白浓度。此外，氯氮平增加了MIF启动子中赖氨酸27残基处组蛋白H3（H3K27）的乙酰化。总之，我们提供了新的证据，表明氯氮平之类的抗精神病药物通过星形胶质细胞中H3K27的乙酰化增加MIF表达，并且MIF可能在抗精神病药物的作用机制中对星形胶质细胞具有潜在作用。
