Interferon-α-induced modulation of glucocorticoid and serotonin receptors as a mechanism of depression
Interferon-α-induced modulation of glucocorticoid and serotonin receptors as a mechanism of depression
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DOI：
10.1016/j.jhep.2005.01.024
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发表时间：
2005-06-01
影响因子：
25.7
通讯作者：
Yoffe, B
中科院分区：
文献类型：
--
作者：
Cai, W;Khaoustov, VI;Yoffe, B
背景/目的：干扰素(IFN) α诱导抑郁的机制尚不清楚。近年来，糖皮质激素受体（GR）和5-羟色胺受体1A （5-HTR1A）的调节参与了导致抑郁症的机制。为了深入了解这一机制，我们评估了ifn - α对GR和5-HTR1A表达的调节作用。方法：用不同剂量的ifn - α处理肝母细胞瘤、髓细胞源性白血病和T细胞源性白血病细胞系，并进行不同孵育时间的Western blot、RT-PCR和微阵列分析。观察到GR和5-HTR1A蛋白和mRNA水平的剂量和时间依赖性降低。结果：在处理6 d的细胞中，GR和5-HTR1A的表达分别下降74%和72%。ifn - α戒断后恢复。与三环抗抑郁药（地西帕明）或5-羟色胺再摄取抑制剂（氟西汀）共孵育可减弱ifn - α对GR或5-HTR1A的影响。GR和5-HTR1A不受ifn - γ或牛磺酸去氧胆酸（TUDCA）治疗的影响。然而，当与TUDCA联合使用时，ifn - α对GR的影响被消除。结论：ifn - α可下调细胞系中GR和5-HTR1A水平。这些GR和5-HTR1A水平，在ifn - α诱导下调后，在停用ifn - α或添加地西帕明或氟西汀后恢复。这些数据为ifn - α诱导抑郁症的发病机制提供了新的见解。(C) 2005年欧洲肝脏研究协会。Elsevier B.V.版权所有。
Background/Aims: The mechanism of interferon (IFN)-alpha-induced depression remains poorly understood. Recently, modulation of glucocorticoid receptor (GR) and serotonin receptor 1A (5-HTR1A) were implicated in mechanism(s) leading to depression. To gain insight into this mechanism, we assessed the effect of IFN-alpha on the modulation of GR and 5-HTR1A expression.Methods: Hepatoblastoma, myelocyte-derived and T cell leukemia-derived cell lines were treated with titrated doses of IFN-alpha for different incubation times and analyzed by Western blot, RT-PCR, and microarrays. Dose- and time-dependent decreases of proteins and mRNA levels of GR and 5-HTR1A were observed.Results: The expression of GR and 5-HTR1A in cells treated for 6 days decreased by 74 and 72%, respectively. Recovery was observed following IFN-alpha withdrawal. Co-incubation with tricyclic antidepressants (desipramine) or serotonin reuptake inhibitors (fluoxetine) attenuated the effect of IFN-alpha on GR or 5-HTR1A. GR and 5-HTR1A were unaffected by treatment with either IFN-gamma or tauroursodeoxycholic acid (TUDCA). However, the effect of IFN-alpha on GR was abolished when used in combination with TUDCA.Conclusions: In conclusion, IFN-alpha downregulated GR and 5-HTR1A levels in cell lines. These levels of GR and 5-HTR1A, following IFN-alpha-induced downregulation, recovered after withdrawal of IFN-alpha or addition of desipramine or fluoxetine. These data provide insights regarding pathogenesis of IFN-alpha-induced depression. (C) 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.