Interferon-Alpha Reduces Human Hippocampal Neurogenesis and Increases Apoptosis via Activation of Distinct STAT1-Dependent Mechanisms.

ABSTRACT: Background:In humans, interferon-? 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-? induces signal transducer and activator of transcription-1 (STAT1) within the hippocampus and disrupts hippocampal neurogenesis. Methods:We used the human hippocampal progenitor cell line HPC0A07/03C to evaluate the effects of 2 concentrations of interferon-?, similar to those observed in human serum during its therapeutic use (500 pg/mL and 5000 pg/mL), on neurogenesis and apoptosis. Results:Both concentrations of interferon-? decreased hippocampal neurogenesis, with the high concentration also increasing apoptosis. Moreover, interferon-? 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-?, 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-?-induced reduction in neurogenesis (potentially through upregulation of the ISGylation-related proteins UBA7, UBE2L6, and HERC5), while IL-6 mediated the interferon-?-induced increase in apoptosis (potentially through downregulation of aquaporin 4). Using transcriptomic analyses, we showed that interferon-? 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). Conclusions:We identify novel molecular mechanisms mediating the effects of interferon-? on the human hippocampus potentially involved in inflammation-induced neuropsychiatric symptoms.

SUBMITTER: Borsini A 

PROVIDER: S-EPMC5793815 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature