Whole genome microarray analysis of DUSP4-deletion reveals a novel role for MAP kinase phosphatase-2 (MKP-2) in macrophage gene expression and function

Thikryat Neamatallah, Shilan Jabbar, Rothwelle Tate, Juliane Schroeder, Muhannad Shweash, James Alexander, Robin Plevin

Research output: Contribution to journalArticle

Abstract

Background: Mitogen-activated protein kinase phosphatase-2 (MKP-2) is a type 1 nuclear dual specific phosphatase (DUSP-4). It plays an important role in macrophage inflammatory responses through the negative regulation of Mitogen activated protein kinase (MAPK) signalling. However, information on the effect of MKP-2 on other aspect of macrophage function is limited. Methods: We investigated the impact of MKP-2 in the regulation of several genes that are involved in function while using comparative whole genome microarray analysis in macrophages from MKP-2 wild type (wt) and knock out (ko) mice. Results: Our data showed that the lack of MKP-2 caused a significant down-regulation of colony-stimulating factor-2 (Csf2) and monocyte to macrophage-associated differentiation (Mmd) genes, suggesting a role of MKP-2 in macrophage development. When treated with macrophage colony stimulating factor (M-CSF), Mmd and Csf2 mRNA levels increased but significantly reduced in ko cells in comparison to wt counterparts. This effect of MKP-2 deletion on macrophage function was also observed by cell counting and DNA measurements. On the signalling level, M-CSF stimulation induced extracellular signal-regulated kinases (ERK) phosphorylation, which was significantly enhanced in the absence of MKP-2. Pharmacological inhibition of ERK reduced both Csf2 and Mmd genes in both wild type and ko cultures, which suggested that enhanced ERK activation in ko cultures may not explain effects on gene expression. Interestingly other functional markers were also shown to be reduced in ko macrophages in comparison to wt mice; the expression of CD115, which is a receptor for M-CSF, and CD34, a stem/progenitor cell marker, suggesting global regulation of gene expression by MKP-2. Conclusions: Transcriptome profiling reveals that MKP-2 regulates macrophage development showing candidate targets from monocyte-to-macrophage differentiation and macrophage proliferation. However, it is unclear whether effects upon ERK signalling are able to explain the effects of DUSP-4 deletion on macrophage function.

LanguageEnglish
Article number3434
Number of pages17
JournalInternational Journal of Molecular Sciences
Volume20
Issue number14
DOIs
Publication statusPublished - 12 Jul 2019

Fingerprint

deletion
phosphatases
macrophages
genome
Macrophages
gene expression
Mitogen-Activated Protein Kinase 1
Phosphatases
Microarray Analysis
Microarrays
Phosphoric Monoester Hydrolases
Gene expression
Phosphotransferases
Genes
Genome
Gene Expression
monocytes
Extracellular Signal-Regulated MAP Kinases
Monocytes
Granulocyte-Macrophage Colony-Stimulating Factor

Keywords

  • MAP Kinase Phosphatase-2
  • DUSP-4
  • macrophages
  • proliferation
  • differentiation

Cite this

@article{9e7fdece0a534b839020dacbf8f9b62f,
title = "Whole genome microarray analysis of DUSP4-deletion reveals a novel role for MAP kinase phosphatase-2 (MKP-2) in macrophage gene expression and function",
abstract = "Background: Mitogen-activated protein kinase phosphatase-2 (MKP-2) is a type 1 nuclear dual specific phosphatase (DUSP-4). It plays an important role in macrophage inflammatory responses through the negative regulation of Mitogen activated protein kinase (MAPK) signalling. However, information on the effect of MKP-2 on other aspect of macrophage function is limited. Methods: We investigated the impact of MKP-2 in the regulation of several genes that are involved in function while using comparative whole genome microarray analysis in macrophages from MKP-2 wild type (wt) and knock out (ko) mice. Results: Our data showed that the lack of MKP-2 caused a significant down-regulation of colony-stimulating factor-2 (Csf2) and monocyte to macrophage-associated differentiation (Mmd) genes, suggesting a role of MKP-2 in macrophage development. When treated with macrophage colony stimulating factor (M-CSF), Mmd and Csf2 mRNA levels increased but significantly reduced in ko cells in comparison to wt counterparts. This effect of MKP-2 deletion on macrophage function was also observed by cell counting and DNA measurements. On the signalling level, M-CSF stimulation induced extracellular signal-regulated kinases (ERK) phosphorylation, which was significantly enhanced in the absence of MKP-2. Pharmacological inhibition of ERK reduced both Csf2 and Mmd genes in both wild type and ko cultures, which suggested that enhanced ERK activation in ko cultures may not explain effects on gene expression. Interestingly other functional markers were also shown to be reduced in ko macrophages in comparison to wt mice; the expression of CD115, which is a receptor for M-CSF, and CD34, a stem/progenitor cell marker, suggesting global regulation of gene expression by MKP-2. Conclusions: Transcriptome profiling reveals that MKP-2 regulates macrophage development showing candidate targets from monocyte-to-macrophage differentiation and macrophage proliferation. However, it is unclear whether effects upon ERK signalling are able to explain the effects of DUSP-4 deletion on macrophage function.",
keywords = "MAP Kinase Phosphatase-2, DUSP-4, macrophages, proliferation, differentiation",
author = "Thikryat Neamatallah and Shilan Jabbar and Rothwelle Tate and Juliane Schroeder and Muhannad Shweash and James Alexander and Robin Plevin",
year = "2019",
month = "7",
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language = "English",
volume = "20",
journal = "International Journal of Molecular Sciences",
issn = "1422-0067",
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}

TY - JOUR

T1 - Whole genome microarray analysis of DUSP4-deletion reveals a novel role for MAP kinase phosphatase-2 (MKP-2) in macrophage gene expression and function

AU - Neamatallah, Thikryat

AU - Jabbar, Shilan

AU - Tate, Rothwelle

AU - Schroeder, Juliane

AU - Shweash, Muhannad

AU - Alexander, James

AU - Plevin, Robin

PY - 2019/7/12

Y1 - 2019/7/12

N2 - Background: Mitogen-activated protein kinase phosphatase-2 (MKP-2) is a type 1 nuclear dual specific phosphatase (DUSP-4). It plays an important role in macrophage inflammatory responses through the negative regulation of Mitogen activated protein kinase (MAPK) signalling. However, information on the effect of MKP-2 on other aspect of macrophage function is limited. Methods: We investigated the impact of MKP-2 in the regulation of several genes that are involved in function while using comparative whole genome microarray analysis in macrophages from MKP-2 wild type (wt) and knock out (ko) mice. Results: Our data showed that the lack of MKP-2 caused a significant down-regulation of colony-stimulating factor-2 (Csf2) and monocyte to macrophage-associated differentiation (Mmd) genes, suggesting a role of MKP-2 in macrophage development. When treated with macrophage colony stimulating factor (M-CSF), Mmd and Csf2 mRNA levels increased but significantly reduced in ko cells in comparison to wt counterparts. This effect of MKP-2 deletion on macrophage function was also observed by cell counting and DNA measurements. On the signalling level, M-CSF stimulation induced extracellular signal-regulated kinases (ERK) phosphorylation, which was significantly enhanced in the absence of MKP-2. Pharmacological inhibition of ERK reduced both Csf2 and Mmd genes in both wild type and ko cultures, which suggested that enhanced ERK activation in ko cultures may not explain effects on gene expression. Interestingly other functional markers were also shown to be reduced in ko macrophages in comparison to wt mice; the expression of CD115, which is a receptor for M-CSF, and CD34, a stem/progenitor cell marker, suggesting global regulation of gene expression by MKP-2. Conclusions: Transcriptome profiling reveals that MKP-2 regulates macrophage development showing candidate targets from monocyte-to-macrophage differentiation and macrophage proliferation. However, it is unclear whether effects upon ERK signalling are able to explain the effects of DUSP-4 deletion on macrophage function.

AB - Background: Mitogen-activated protein kinase phosphatase-2 (MKP-2) is a type 1 nuclear dual specific phosphatase (DUSP-4). It plays an important role in macrophage inflammatory responses through the negative regulation of Mitogen activated protein kinase (MAPK) signalling. However, information on the effect of MKP-2 on other aspect of macrophage function is limited. Methods: We investigated the impact of MKP-2 in the regulation of several genes that are involved in function while using comparative whole genome microarray analysis in macrophages from MKP-2 wild type (wt) and knock out (ko) mice. Results: Our data showed that the lack of MKP-2 caused a significant down-regulation of colony-stimulating factor-2 (Csf2) and monocyte to macrophage-associated differentiation (Mmd) genes, suggesting a role of MKP-2 in macrophage development. When treated with macrophage colony stimulating factor (M-CSF), Mmd and Csf2 mRNA levels increased but significantly reduced in ko cells in comparison to wt counterparts. This effect of MKP-2 deletion on macrophage function was also observed by cell counting and DNA measurements. On the signalling level, M-CSF stimulation induced extracellular signal-regulated kinases (ERK) phosphorylation, which was significantly enhanced in the absence of MKP-2. Pharmacological inhibition of ERK reduced both Csf2 and Mmd genes in both wild type and ko cultures, which suggested that enhanced ERK activation in ko cultures may not explain effects on gene expression. Interestingly other functional markers were also shown to be reduced in ko macrophages in comparison to wt mice; the expression of CD115, which is a receptor for M-CSF, and CD34, a stem/progenitor cell marker, suggesting global regulation of gene expression by MKP-2. Conclusions: Transcriptome profiling reveals that MKP-2 regulates macrophage development showing candidate targets from monocyte-to-macrophage differentiation and macrophage proliferation. However, it is unclear whether effects upon ERK signalling are able to explain the effects of DUSP-4 deletion on macrophage function.

KW - MAP Kinase Phosphatase-2

KW - DUSP-4

KW - macrophages

KW - proliferation

KW - differentiation

UR - https://www.mdpi.com/journal/ijms

U2 - 10.3390/ijms20143434

DO - 10.3390/ijms20143434

M3 - Article

VL - 20

JO - International Journal of Molecular Sciences

T2 - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1422-0067

IS - 14

M1 - 3434

ER -