Thesis

The role of mitogen-activated protein kinase phosphatase-2 (MKP-2) in macrophage development and gene expression

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Awarding institution
  • University of Strathclyde
Date of award
  • 2014
Thesis identifier
  • T13785
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Abstract
  • Mitogen-activated protein kinase phosphatase-2 (MKP-2) is a type 1 nuclear dual specific phosphatase (DUSP4) and an important immune regulator. It specifically dephosphorylates the MAP kinases ERK and JNK to influence pro- and antiinflammatory cytokine production. MKP-2 has recently been shown to play a significant role in controlling Leishmania mexicana infection (Al-Mutairi et al., 2010) primarily by influencing macrophage activity. However, information on the effect of MKP-2 deletion at the molecular level on macrophage development and function is limited. This project utilised a novel DUSP4 gene knockout mouse and investigated the effects of MKP-2 deletion on M-CSF induced MAPK signalling and macrophage development as well as macrophage gene expression. Experiments in bone marrow derived macrophages demonstrated that in response to M-CSF macrophage, proliferation was reduced following to MKP-2 deletion. This was correlated with ERK phosphorylation, the expression of CD115 and CD34 on macrophage progenitors as well as the induction of genes related to macrophage differentiation and proliferation, colony stimulating factor-2 (Csf2) and monocyte to macrophage differentiation associated (Mmd) genes. In addition a comparative microarray gene expression analysis was conducted on MKP-2-/- and MKP-2+/+ macrophages following (LPS) or (IL-4) activation. As demonstrated previously, and associated with a role for MKP-2 in antimicrobial activity, arginase-1 expression was up-regulated in MKP-2-/- compared with MKP- 2+/+ macrophages. Surprisingly, and in contrast, we found that other alternative activation markers Ym1 (Chi3l3) and Fizz1/Retnla (Relm-α) were significantly reduced in MKP-2-/- macrophages when compared with their wild-type counterparts. As both Ym1 and Fizz1 have been implicated to play a major role in extracellular matrix disposition this suggests a significant role for MKP-2 in wound healing. Collectively, the findings in the current study have established that MKP-2 plays an important role in macrophage development and immune function.
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DOI
Date Created
  • 2014
Former identifier
  • 1036464

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