About this item:

231 Views | 240 Downloads

Author Notes:

E-mail: Daniel.ambruso@ucdenver.edu

Michael A. Ellison and Christy M. Gearheart contributed equally to this work.

Author Contributions: Conceptualization: Michael A. Ellison, Daniel R. Ambruso.

Data curation: Michael A. Ellison, Christy M. Gearheart.

Formal analysis: Michael A. Ellison, Christy M. Gearheart.

Funding acquisition: Daniel R. Ambruso.

Investigation: Michael A. Ellison, Christy M. Gearheart.

Methodology: Michael A. Ellison.

Project administration: Christopher C. Porter.

Resources: Christopher C. Porter.

Software: Christy M. Gearheart.

Supervision: Daniel R. Ambruso.

Writing – original draft: Michael A. Ellison.

Writing – review & editing: Michael A. Ellison, Christy M. Gearheart, Daniel R. Ambruso.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Daniel R. Ambruso has served as an educational consultant for Horizon Pharma Ltd. Ireland.

These studies are investigator initiated and funded by Horizon Oharma Ltd. Ireland.

This does not alter our adheremce to all the PLOS ONE policies on sharing data and materials.

Subjects:

Research Funding:

This work was supported by the Horizon Pharma Ireland Ltd to DRA, the Stacey True Memorial Trust to DRA and the Genomics and Microarray Shared Resource of Colorado’s National Institute of Health/National Cancer Institute Cancer Center Support Grant P30CA046934.

No funding to any authors, the funding was to the core facility where microarray studies were carried out

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • MHC CLASS-II
  • CHRONIC GRANULOMATOUS-DISEASE
  • COLONY-STIMULATING FACTOR
  • TOLL-LIKE RECEPTORS
  • NOD-LIKE RECEPTORS
  • INTERFERON-GAMMA
  • POLYMORPHONUCLEAR NEUTROPHILS
  • INNATE IMMUNITY
  • T-LYMPHOCYTES
  • RECOGNITION RECEPTOR
  • Neutrophils
  • Apoptosis
  • Antigen presentation
  • Gene expression
  • Cytokines
  • T cells
  • Antigen-presenting cells
  • Immune receptors

IFN-gamma alters the expression of diverse immunity related genes in a cell culture model designed to represent maturing neutrophils

Tools:

Journal Title:

PLoS ONE

Volume:

Volume 12, Number 10

Publisher:

, Pages e0185956-e0185956

Type of Work:

Article | Final Publisher PDF

Abstract:

The cytokine interferon-γ (IFN-γ) is approved as a drug to treat chronic granulomatous disease (CGD) and osteopetrosis and is also used in hyperimmunoglobulin E syndromes. Patients with CGD have defects in proteins of the NOX2 NADPH oxidase system. This leads to reduced production of microbicidal ROS by PMNs and recurrent life threatening infections. The goal of this study was to better understand how IFN-γ might support phagocyte function in these diseases, and to obtain information that might expand potential uses for IFN-γ. Neutrophils mature in the bone marrow and then enter the blood where they quickly undergo apoptotic cell death with a half-life of only 5–10 hours. Therefore we reasoned that IFN-γ might exert its effects on neutrophils via prolonged exposure to cells undergoing maturation in the marrow rather than by its brief exposure to short-lived circulating cells. To explore this possibility we made use of PLB-985 cells, a myeloblast-like myeloid cell line that can be differentiated into a mature, neutrophil-like state by treatment with various agents including DMSO. In initial studies we investigated transcription and protein expression in PLB-985 cells undergoing maturation in the presence or absence of IFN-γ. We observed IFN-γ induced differences in expression of genes known to be involved in classical aspects of neutrophil function (transmigration, chemotaxis, phagocytosis, killing and pattern recognition) as well as genes involved in apoptosis and other mechanisms that regulating neutrophil number. We also observed differences for genes involved in the major histocompatibility complex I (MHCI) and MHCII systems whose involvement in neutrophil function is controversial and not well defined. Finally, we observed significant changes in expression of genes encoding guanylate binding proteins (Gbps) that are known to have roles in immunity but which have not as yet been linked to neutrophil function. We propose that changes in the expression within these classes of genes could help explain the immune supportive effects of IFN-γ. Next we explored if the effect of IFN-γ on expression of these genes is dependent on whether the cells are undergoing maturation; to do this we compared the effects of IFN-γ on cells cultured with and without DMSO. For a subset of genes the expression level changes caused by IFN-γ were much greater in maturing cells than non-maturing cells. These findings indicate that developmental changes associated with cell maturation can modulate the effects of IFN-γ but that this is gene specific. Since the effects of IFN-γ depend on whether cells are maturing, the gene expression changes observed in this study must be due to more than just prolonged application of IFN-γ and are instead the result of interplay between cell maturation and changes caused by the chemokine. This supports our hypothesis that the effects of IFN-γ on developing neutrophils in the bone marrow may be very different from its effects on mature cells in the blood. Collectively the findings in this study enhance our understanding of the effects of IFN-γ on maturing myeloid cells and indicate possible mechanisms by which this cytokine could support immune function.

Copyright information:

© 2017 Ellison et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
Export to EndNote