Section of Stress, Psychiatry and Immunology and Perinatal Psychiatry, King's College London, London, United Kingdom.
Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, London, United Kingdom.
Int J Neuropsychopharmacol. 2018 Feb 1;21(2):187-200. doi: 10.1093/ijnp/pyx083.
In humans, interferon-α treatment for chronic viral hepatitis is a well-recognized clinical model for inflammation-induced depression, but the molecular mechanisms underlying these effects are not clear. Following peripheral administration in rodents, interferon-α induces signal transducer and activator of transcription-1 (STAT1) within the hippocampus and disrupts hippocampal neurogenesis.
We used the human hippocampal progenitor cell line HPC0A07/03C to evaluate the effects of 2 concentrations of interferon-α, similar to those observed in human serum during its therapeutic use (500 pg/mL and 5000 pg/mL), on neurogenesis and apoptosis.
Both concentrations of interferon-α decreased hippocampal neurogenesis, with the high concentration also increasing apoptosis. Moreover, interferon-α increased the expression of interferon-stimulated gene 15 (ISG15), ubiquitin-specific peptidase 18 (USP18), and interleukin-6 (IL-6) via activation of STAT1. Like interferon-α, co-treatment with a combination of ISG15, USP18, and IL-6 was able to reduce neurogenesis and enhance apoptosis via further downstream activation of STAT1. Further experiments showed that ISG15 and USP18 mediated the interferon-α-induced reduction in neurogenesis (potentially through upregulation of the ISGylation-related proteins UBA7, UBE2L6, and HERC5), while IL-6 mediated the interferon-α-induced increase in apoptosis (potentially through downregulation of aquaporin 4). Using transcriptomic analyses, we showed that interferon-α regulated pathways involved in oxidative stress and immune response (e.g., Nuclear Factor (erythroid-derived 2)-like 2 [Nrf2] and interferon regulatory factor [IRF] signaling pathway), neuronal formation (e.g., CAMP response element-binding protein [CREB] signaling), and cell death regulation (e.g., tumor protein(p)53 signaling).
We identify novel molecular mechanisms mediating the effects of interferon-α on the human hippocampus potentially involved in inflammation-induced neuropsychiatric symptoms.
在人类中，干扰素-α治疗慢性病毒性肝炎是一种公认的炎症诱导抑郁的临床模型，但这些影响的分子机制尚不清楚。在啮齿动物外周给药后，干扰素-α在海马体内诱导信号转导和转录激活因子 1（STAT1），并破坏海马神经发生。
我们使用人海马祖细胞系 HPC0A07/03C 来评估两种浓度的干扰素-α（类似于其在治疗用途中在人血清中观察到的浓度（500pg/mL 和 5000pg/mL））对神经发生和细胞凋亡的影响。
两种浓度的干扰素-α均降低了海马神经发生，高浓度也增加了细胞凋亡。此外，干扰素-α通过激活 STAT1，增加干扰素刺激基因 15（ISG15）、泛素特异性肽酶 18（USP18）和白细胞介素 6（IL-6）的表达。与干扰素-α一样，ISG15、USP18 和 IL-6 的联合治疗也能够通过进一步下游激活 STAT1 来减少神经发生并增强细胞凋亡。进一步的实验表明，ISG15 和 USP18 介导了干扰素-α诱导的神经发生减少（可能通过上调 ISGylation 相关蛋白 UBA7、UBE2L6 和 HERC5），而 IL-6 介导了干扰素-α诱导的细胞凋亡增加（可能通过下调水通道蛋白 4）。通过转录组分析，我们表明干扰素-α调节了涉及氧化应激和免疫反应的途径（例如，核因子（红细胞衍生 2）样 2（Nrf2）和干扰素调节因子（IRF）信号通路）、神经元形成（例如，cAMP 反应元件结合蛋白（CREB）信号通路）和细胞死亡调节（例如，肿瘤蛋白（p）53 信号通路）。
我们确定了介导干扰素-α对人海马体影响的新分子机制，这些机制可能与炎症诱导的神经精神症状有关。
