Molecular signatures of peripheral blood mononuclear cells during chronic interferon-α treatment: relationship with depression and fatigue.
Molecular signatures of peripheral blood mononuclear cells during chronic interferon-α treatment: relationship with depression and fatigue.
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DOI：
10.1017/s0033291711002868
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发表时间：
2012-08
影响因子：
6.9
通讯作者：
Miller, A. H.
中科院分区：
文献类型：
--
作者：
Felger, J. C.;Cole, S. W.;Pace, T. W. W.;Hu, F.;Woolwine, B. J.;Doho, G. H.;Raison, C. L.;Miller, A. H.
干扰素(IFN)- α治疗传染性疾病和癌症导致高抑郁和疲劳率，并已被用于研究炎症细胞因子对大脑和行为的影响。然而，对于体内慢性ifn - α对免疫细胞的转录影响及其与ifn - α诱导的行为改变的关系知之甚少。研究人员对21名慢性丙型肝炎患者的外周血单个核细胞进行了全基因组转录谱分析，这些患者要么等待ifn - α治疗（n=10），要么接受ifn - α治疗12周（n=11）。微阵列数据的显著性分析鉴定出252个上调基因转录本和116个下调基因转录本。在上调的基因中，与慢性疲劳综合征（CFS）相关的2'-5'-寡聚腺苷酸合成酶2 （OAS2）是唯一在ifn - α诱导的抑郁/疲劳患者中差异表达的基因，并与12周时的抑郁和疲劳评分相关（r=0.80, p=0.003和r=0.70, p=0.017）。基于启动子的生物信息学分析将ifn - α相关的转录改变与主要来源于单核细胞和浆细胞样树突状细胞的髓系分化、ifn - α信号传导、AP1和CREB/ATF通路中的转录因子联系起来。ifn - α治疗的高抑郁/疲劳评分患者表现出骨髓分化、ifn - α和AP1信号转录因子启动子基序基因上调，CREB/ATF基序患病率降低，这与重度抑郁症有关。慢性ifn - α给药期间的抑郁和疲劳与与行为障碍（包括CFS和重度抑郁症）相关的基因的表达（OAS2）和转录控制（CREB/ATF）的改变相关，进一步支持免疫对这些疾病的贡献。
Interferon (IFN)-alpha treatment for infectious disease and cancer causes high rates of depression and fatigue, and has been used to investigate the impact of inflammatory cytokines on brain and behavior. However, little is known about the transcriptional impact of chronic IFN-alpha on immune cells in vivo and its relationship to IFN-alpha-induced behavioral changes. Genome-wide transcriptional profiling was performed on peripheral blood mononuclear cells from 21 patients with chronic hepatitis C either awaiting IFN-alpha therapy (n=10) or at 12 weeks of IFN-alpha treatment (n=11). Significance analysis of microarray data identified 252 up-regulated and 116 down-regulated gene transcripts. Of up-regulated genes, 2'-5'-oligoadenylate synthetase 2 (OAS2), a gene linked to chronic fatigue syndrome (CFS), was the only gene that was differentially expressed in patients with IFN-alpha-induced depression/fatigue, and correlated with depression and fatigue scores at 12 weeks (r=0.80, p=0.003 and r=0.70, p=0.017, respectively). Promoter-based bioinformatic analyses linked IFN-alpha-related transcriptional alterations to transcription factors involved in myeloid differentiation, IFN-alpha signaling, AP1 and CREB/ATF pathways, which were derived primarily from monocytes and plasmacytoid dendritic cells. IFN-alpha-treated patients with high depression/fatigue scores demonstrated up-regulation of genes bearing promoter motifs for transcription factors involved in myeloid differentiation, IFN-alpha and AP1 signaling, and reduced prevalence of motifs for CREB/ATF, which has been implicated in major depression. Depression and fatigue during chronic IFN-alpha administration were associated with alterations in the expression (OAS2) and transcriptional control (CREB/ATF) of genes linked to behavioral disorders including CFS and major depression, further supporting an immune contribution to these diseases.