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

PLoS One. 2013 Apr 23;8(4):e62366. doi: 10.1371/journal.pone.0062366. Print 2013.

Abstract

Background: 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 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-α and overnight exposure to IFN-β. 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-β that are modulated by TNF-α in monocytes, such as RIPK2 and CD83, but not in T cells or PBMCs. Known IFN-β 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-β 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-β response pathways and genes, some of which were monocytes specific; second, a cell-specific modulation of the IFN-β response transcriptome by TNF-α.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-ribosyl Cyclase 1 / genetics
  • ADP-ribosyl Cyclase 1 / metabolism
  • Cluster Analysis
  • Gene Expression Profiling*
  • Gene Expression Regulation / drug effects*
  • Gene Regulatory Networks
  • Humans
  • Interferon-beta / pharmacology*
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Monocytes / drug effects*
  • Monocytes / metabolism*
  • Organ Specificity
  • Reproducibility of Results
  • Signal Transduction
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / metabolism*
  • Transcription, Genetic
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Tumor Necrosis Factor-alpha
  • Interferon-beta
  • ADP-ribosyl Cyclase 1

Grant support

This study was supported by the Wolfson Family Charitable Trust, the Sacta-Rashi Foundation, Galil Center for Medical Informatics, Telemedicine and Personalized Medicine, and the Adelis Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.