title: 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.
authors.affiliation: Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Nakakoma-gun, Yamanashi, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Kaneko
authors.forename: Koutaro
authors.initials: K
authors.lastname: Kudo
authors.forename: Tadashi
authors.initials: T
authors.lastname: Mabuchi
authors.forename: Keiko
authors.initials: K
authors.lastname: Takemoto
authors.forename: Koichiro
authors.initials: K
authors.lastname: Fujimaki
authors.forename: Henny
authors.initials: H
authors.lastname: Wati
authors.forename: Hironobu
authors.initials: H
authors.lastname: Iguchi
authors.forename: Hideo
authors.initials: H
authors.lastname: Tezuka
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Kanba
mesh_terms: D000818:Animals; D001973:Bromodeoxyuridine; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects*; D018891:Dentate Gyrus / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D003866:Depressive Disorder / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D007155:Immunologic Factors / Q000009:adverse effects; D016898:Interferon-alpha / Q000009:adverse effects*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053583:Interleukin-1beta / Q000819:agonists* / Q000276:immunology / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: D007155:Immunologic Factors; D016898:Interferon-alpha; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D017472:Receptors, Interleukin-1; D001973:Bromodeoxyuridine