Suppression of cell proliferation by interferon-alpha through interleukin-1 production in adult rat dentate gyrus.
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.
Kaneko
Naoko
N
Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Nakakoma-gun, Yamanashi, Japan.
Kudo
Koutaro
K
Mabuchi
Tadashi
T
Takemoto
Keiko
K
Fujimaki
Koichiro
K
Wati
Henny
H
Iguchi
Hironobu
H
Tezuka
Hideo
H
Kanba
Shigenobu
S
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
D007155:Immunologic Factors; D016898:Interferon-alpha; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D017472:Receptors, Interleukin-1; D001973:Bromodeoxyuridine