Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Molecular signatures of peripheral blood mononuclear cells following chronic IFN-alpha: Relationship of OAS2 with Depression and Fatigue

ABSTRACT: Interferon (IFN)-alpha causes high rates of depression and fatigue, and is used to investigate the impact of innate immune cytokines on brain and behavior. However, little is known about transcriptional profiles of circulating immune cells during chronic IFN-alpha administration. Accordingly, genome-wide transcriptional profiling was performed on peripheral blood mononuclear cells from 21 patients with chronic hepatitis C virus either awaiting IFN-alpha therapy (n=10) or after 12 weeks of IFN-alpha treatment (n=11). Significance analysis of microarray data identified 252 up-regulated gene transcripts, the majority of which were related to IFN-alpha/antiviral or innate-immune/inflammatory signaling. Of these upregulated genes, 2'-5'-oligoadenylate synthetase 2 (OAS2) was the only gene that was differentially expressed in patients that developed IFN-alpha-induced depression/fatigue, and correlated with depression and fatigue scores at 12 weeks of IFN-alpha administration. Promoter-based bioinformatic and cellular origin analyses revealed IFN-alpha-induced increases in genes bearing transcription factor binding motifs (TFBMs) related to myeloid differentiation, IFN-alpha signaling, API and CREB/ATF family of transcription pathways, with changes derived primarily from monocytes and plasmacytoid dendritic cells. Patients with high depression/fatigue scores demonstrated up-regulation of genes bearing TFBMs for myeloid differentiation, IFN-alpha and AP1 signaling, and down regulation of TFBMs for CREB/ATF-related transcription factors. Cellular origin analyses indicated a shift toward genes derived from CD8+T and NK cells in subjects with high depression/fatigue scores. These results reveal an antiviral and inflammatory transcriptional profile after 12 weeks IFN-alpha, accompanied by increased OAS2 expression, decreased CREB/ATF transcriptional control, and a shift from monocyte-derived genes to those of cytotoxic lymphocytes in IFN-alpha-induced depression/fatigue. Total RNA was isolated from the peripheral blood mononuclear cells (PBMC) obtained at 12 weeks from HCV patients treated with IFN-alpha plus ribavirin (n=11) and untreated HCV patients awaiting IFN-alpha/ribavirin therapy (control subjects, n=10).

ORGANISM(S): Homo sapiens

SUBMITTER: Gregory Doho

PROVIDER: E-GEOD-31187 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Molecular signatures of peripheral blood mononuclear cells during chronic interferon-α treatment: relationship with depression and fatigue.

Felger J C JC Cole S W SW Pace T W W TW Hu F F Woolwine B J BJ Doho G H GH Raison C L CL Miller A H AH

Psychological medicine 20111209 8

<h4>Background</h4>Interferon-alpha (IFN-α) 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-α on immune cells in vivo and its relationship to IFN-α-induced behavioral changes.<h4>Method</h4>Genome-wide transcriptional profiling was performed on peripheral blood mononuclear cells (PBMCs) from ...[more]

PMID: 22152193

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Project description:Interferon (IFN)-alpha causes high rates of depression and fatigue, and is used to investigate the impact of innate immune cytokines on brain and behavior. However, little is known about transcriptional profiles of circulating immune cells during chronic IFN-alpha administration. Accordingly, genome-wide transcriptional profiling was performed on peripheral blood mononuclear cells from 21 patients with chronic hepatitis C virus either awaiting IFN-alpha therapy (n=10) or after 12 weeks of IFN-alpha treatment (n=11). Significance analysis of microarray data identified 252 up-regulated gene transcripts, the majority of which were related to IFN-alpha/antiviral or innate-immune/inflammatory signaling. Of these upregulated genes, 2'-5'-oligoadenylate synthetase 2 (OAS2) was the only gene that was differentially expressed in patients that developed IFN-alpha-induced depression/fatigue, and correlated with depression and fatigue scores at 12 weeks of IFN-alpha administration. Promoter-based bioinformatic and cellular origin analyses revealed IFN-alpha-induced increases in genes bearing transcription factor binding motifs (TFBMs) related to myeloid differentiation, IFN-alpha signaling, API and CREB/ATF family of transcription pathways, with changes derived primarily from monocytes and plasmacytoid dendritic cells. Patients with high depression/fatigue scores demonstrated up-regulation of genes bearing TFBMs for myeloid differentiation, IFN-alpha and AP1 signaling, and down regulation of TFBMs for CREB/ATF-related transcription factors. Cellular origin analyses indicated a shift toward genes derived from CD8+T and NK cells in subjects with high depression/fatigue scores. These results reveal an antiviral and inflammatory transcriptional profile after 12 weeks IFN-alpha, accompanied by increased OAS2 expression, decreased CREB/ATF transcriptional control, and a shift from monocyte-derived genes to those of cytotoxic lymphocytes in IFN-alpha-induced depression/fatigue.

Project description:A novel assay was developed for Daudi cells in which the antiviral (AV) and antiproliferative (AP) activities of interferon (IFN) can be measured simultaneously. Using this novel assay, conditions allowing IFN AV protection but no growth inhibition were identified and selected. Daudi cells were treated under these conditions, and gene expression microarray analyses were performed. The results of the analysis identified 25 genes associated with IFN-alpha AV activity. Upregulation of 23 IFN-induced genes was confirmed by using reverse transcription-PCR. Of 25 gene products, 17 were detected by Western blotting at 24 h. Of the 25 genes, 10 have not been previously linked to AV activity of IFN-alpha. The most upregulated gene was IFIT3 (for IFN-induced protein with tetratricopeptide repeats 3). The results from antibody neutralizing experiments suggested an association of the identified genes with IFN-alpha AV activity. This association was strengthened by results from IFIT3-small interfering RNA transfection experiments showing decreased expression of IFIT3 and a reduction in the AV activity induced by IFN-alpha. Overexpression of IFIT3 resulted in a decrease of virus titer. Transcription of AV genes after the treatment of cells with higher concentrations of IFN having an AP effect on Daudi cells suggested pleiotropic functions of identified gene products. Gene expression was initially measured in four Daudi cell groups (3 x 10(6) in 10 ml of RPMI) treated for 24 h at IFN concentrations selected to allow comparison of gene activity in AV activity environments with environments in which no AV activity was observed. These treatment groups were: (i) 0.0036 ng of IFN-alpha2c/ml (n=5) (allowing AV activity only); (ii) 0.00036 ng of IFN-alpha2c/ml (n=5) (no AV observed); (iii) 0.036 ng of HY-2/ml (n=3) (allowing AV activity); and (iv) 0.0036 ng of HY-2/ml (n=3) (no AV observed). To refine the list of genes associated with AV activity, samples showing AP phenotype (achieved by treatment with IFN-alpha2c [0.36 ng/ml] (n=3) or HY-2 [36 ng/ml]) (n=3) were compared to identically treated samples manipulated to display the AV phenotype through subsequent neutralization with anti-IFNAR1 MAb 64.10 (1 ug/ml) (n=6). Further analysis of gene expression profiles after 6 h of incubation helped indicate genes associated with early roles in IFN-induced AV mechanisms (n=6).

Dataset Information

Molecular signatures of peripheral blood mononuclear cells following chronic IFN-alpha: Relationship of OAS2 with Depression and Fatigue

Publications

Molecular signatures of peripheral blood mononuclear cells during chronic interferon-α treatment: relationship with depression and fatigue.

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