1. ¹Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Nakakoma-gun, Yamanashi, Japan
2. ²Departments of Neuropsychiatry and Clinical Ethics, Faculty of Medicine, University of Yamanashi, Nakakoma-gun, Yamanashi, Japan
3. ³Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
4. ⁴Department of Biochemistry, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Nakakoma-gun, Yamanashi, Japan
5. ⁵Prefectural University of Hiroshima, Faculty of Health and Welfare, Mihara, Japan
6. ⁶Laboratory Animal Support Section, Center for Life Science Research, University of Yamanashi, Nakakoma-gun,Yamanashi, Japan
7. ⁷Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Higashiku, Fukuoka, Japan

Correspondence: Dr K Kudo, Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Tel: +81 3 3815 5411; Fax: +81 20 4666 0138; E-mail: koutarok-tky@umin.ac.jp

Received 27 December 2005; Revised 5 April 2006; Accepted 16 May 2006; Published online 5 July 2006.

Abstract

The therapeutic use of interferon-alpha (IFN-), a proinflammatory cytokine, is known to cause various neuropsychiatric adverse effects. In particular, depression occurs in 30–45% of patients, frequently interrupting treatment. IFN--treated animals also show depression-like behaviors. However, mechanisms underlying the depression caused by IFN- 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- treatment on neurogenesis in the adult rat dentate gyrus (DG). Immediately after the administration of IFN- 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-1), a major proinflammatory cytokine, was observed in the hippocampus following the administration of IFN-. Furthermore, coadministration of an IL-1 receptor antagonist completely blocked the IFN--induced suppression of the cell-proliferative activity in the DG. Our results indicate that IFN- suppresses neurogenesis in the DG, and that IL-1 plays an essential role in the suppression. The decreased cell proliferation caused by IFN--induced IL-1 may be responsible, at least in part, for IFN--induced depression.