Suppression of Cell Proliferation by Interferon-Alpha through Interleukin-1 Production in Adult Rat Dentate Gyrus

Abstract

The therapeutic use of interferon-alpha (IFN-alpha), a proinflammatory cytokine, is known to cause various neuropsychiatric adverse effects. In particular, depression occurs in 30-45% of patients, frequently interrupting treatment. IFN-alpha-treated animals also show depression-like behaviors. However, mechanisms underlying the depression caused by IFN-alpha remain to be defined. Recently, a decrease in adult hippocampal neurogenesis was revealed as a possible neuropathological mechanism of depression. Therefore, we investigated the effect of subchronic IFN-alpha treatment on neurogenesis in the adult rat dentate gyrus (DG). Immediately after the administration of IFN-alpha for 1 week, a decrease in the number of 5-bromo-deoxyuridine-labeled proliferating cells was observed in the DG; however, no effect was detected on the expression of mature neuronal phenotype in the newly formed cells 3 weeks later. Also, an increase in the level of interleukin-1beta (IL-1beta), a major proinflammatory cytokine, was observed in the hippocampus following the administration of IFN-alpha. Furthermore, coadministration of an IL-1 receptor antagonist completely blocked the IFN-alpha-induced suppression of the cell-proliferative activity in the DG. Our results indicate that IFN-alpha suppresses neurogenesis in the DG, and that IL-1beta plays an essential role in the suppression. The decreased cell proliferation caused by IFN-alpha-induced IL-1beta may be responsible, at least in part, for IFN-alpha-induced depression.