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Interferon-beta induces distinct gene expression response patterns in human monocytes versus T cells.

ABSTRACT: BACKGROUND: Monocytes, which are key players in innate immunity, are outnumbered by neutrophils and lymphocytes among peripheral white blood cells. The cytokine interferon-? (IFN-?) is widely used as an immunomodulatory drug for multiple sclerosis and its functional pathways in peripheral blood mononuclear cells (PBMCs) have been previously described. The aim of the present study was to identify novel, cell-specific IFN-? functions and pathways in tumor necrosis factor (TNF)-?-activated monocytes that may have been missed in studies using PBMCs. METHODOLOGY/PRINCIPAL FINDINGS: Whole genome gene expression profiles of human monocytes and T cells were compared following in vitro priming to TNF-? and overnight exposure to IFN-?. Statistical analyses of the gene expression data revealed a cell-type-specific change of 699 transcripts, 667 monocyte-specific transcripts, 21 T cell-specific transcripts and 11 transcripts with either a difference in the response direction or a difference in the magnitude of response. RT-PCR revealed a set of differentially expressed genes (DEGs), exhibiting responses to IFN-? that are modulated by TNF-? in monocytes, such as RIPK2 and CD83, but not in T cells or PBMCs. Known IFN-? promoter response elements, such as ISRE, were enriched in T cell DEGs but not in monocyte DEGs. The overall directionality of the gene expression regulation by IFN-? was different in T cells and monocytes, with up-regulation more prevalent in T cells, and a similar extent of up and down-regulation recorded in monocytes. CONCLUSIONS: By focusing on the response of distinct cell types and by evaluating the combined effects of two cytokines with pro and anti-inflammatory activities, we were able to present two new findings First, new IFN-? response pathways and genes, some of which were monocytes specific; second, a cell-specific modulation of the IFN-? response transcriptome by TNF-?.

SUBMITTER: Henig N

PROVIDER: S-EPMC3633862 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Interferon-beta induces distinct gene expression response patterns in human monocytes versus T cells.

Henig Noa N Avidan Nili N Mandel Ilana I Staun-Ram Elsebeth E Ginzburg Elizabeta E Paperna Tamar T Pinter Ron Y RY Miller Ariel A

PloS one 20130423 4

<h4>Background</h4>Monocytes, which are key players in innate immunity, are outnumbered by neutrophils and lymphocytes among peripheral white blood cells. The cytokine interferon-β (IFN-β) is widely used as an immunomodulatory drug for multiple sclerosis and its functional pathways in peripheral blood mononuclear cells (PBMCs) have been previously described. The aim of the present study was to identify novel, cell-specific IFN-β functions and pathways in tumor necrosis factor (TNF)-α-activated m ...[more]

PMID: 23626809

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Project description:Previously, we demonstrated in test and validation cohorts that type I IFN (T1IFN) activity can predict non-response to tumor necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA). In this study, we examine the biology of non-classical and classical monocytes from RA patients defined by their pre-biologic treatment T1IFN activity. We compared single cell gene expression in purified classical (CL, n = 342) and non-classical (NC, n = 359) monocytes. In our previous work, RA patients who had either high IFN?/? activity (>1.3) or undetectable T1IFN were likely to have EULAR non-response to TNFi. In this study comparisons were made among patients grouped according to their pre-biologic treatment T1IFN activity as clinically relevant: "T1IFN undetectable (T1IFN ND) or IFN?/? >1.3" (n = 9) and "T1IFN detectable but IFN?/? ? 1.3" (n = 6). In addition, comparisons were made among patients grouped according to their T1IFN activity itself: "T1IFN ND," "T1IFN detected and IFN?/? ? 1.3," and "IFN?/? >1.3." Major differences in gene expression were apparent in principal component and unsupervised cluster analyses. CL monocytes from the T1IFN ND or IFN?/? >1.3 group were unlikely to express JAK1 and IFI27 (p < 0.0001 and p 0.0005, respectively). In NC monocytes from the same group, expression of IFNAR1, IRF1, TNFA, TLR4 (p ? 0.0001 for each) and others was enriched. Interestingly, JAK1 expression was absent in CL and NC monocytes from nine patients. This pattern most strongly associated with the IFN?/?>1.3 group. Differences in gene expression in monocytes among the groups suggest differential IFN pathway activation in RA patients who are either likely to respond or to have no response to TNFi. Additional transcripts enriched in NC cells of those in the T1IFN ND and IFN?/? >1.3 groups included MYD88, CD86, IRF1, and IL8. This work could suggest key pathways active in biologically defined groups of patients, and potential therapeutic strategies for those patients unlikely to respond to TNFi.

Project description:The research hypothesis was that the unique expression profile of monocytes in response to Interferon-beta (IFN-Î²) might be masked by the response profile of the more abundant T cells. The analysis of monocytes response may highlight novel IFN-Î² functions and pathways that have not been recognized previously. The aim of this study was to characterized the IFN-Î² transcriptional response in monocytes, a small but influential cell-subset, using gene expression profile and pathway analysis. The expression profiles of purified human monocytes and T cells pulse with IFN-Î² overnight were compared, and revealed 276 and 42 Differentially Expressed Genes (DEGs) in monocytes and T cells respectively, with only 5 genes common to both sets. Many of the DEGs detected in monocytes were novel with respect to the recognized IFN-Î² response, and included genes involved in immune-specific activities, communication between cells, regulation of apoptosis, cell migration, and protein translation. Network and pathway analysis of the T cells response revealed the familiar immune pathways, response to virus pathways, and IFN canonical pathway. In monocytes, however, we detected along with known IFN-Î²-related pathways, such as cell migration also pathways that had not been previously described in the context of IFN-Î² response, such as the High-Mobility Group Box-1 (HMGB1) signaling pathway. However, most DEGs in monocytes did not cluster to specific networks or canonical pathways. The monocyte-specific DEGs and pathways described herein are beyond the current knowledge regarding the biology of the IFN-Î² response and the differential response to IFN-Î² of monocytes versus T cells described emphasizes the importance of cell-specific studies for elucidating the spectrum of cytokine-mediated immunomodulation. Monocytes and T lymphocytes were isolated from 3 healthy volunteers. For each sample the expression profile of untreated cells was compared to the profile of IFN-Î² treated cells, i.e. 4 samples from each donor (2 cell types, with and without treatment), 12 samples total.

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Interferon-beta induces distinct gene expression response patterns in human monocytes versus T cells.

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Interferon-beta induces distinct gene expression response patterns in human monocytes versus T cells.

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