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Title The role of mitogen-activated protein kinase phosphate-2 (MKP-2) in macrophage functions / by Shilan Khayrula Jabbar.
Name Jabbar, Shilan Khayrula. .
Abstract Mitogen-activated protein kinase phosphatase-2 (MKP-2) is a type 1 nuclear dual specificity phosphatase which known to play key roles in cellular function through dephosphorylation of the MAPKs (ERK, JNK and p38). MKP-2 has recently been shown to play a significant role in the immune response following parasite and bacterial infections. However, the effect of MKP-2 deletion on a number of other key macrophages functions including phagocytosis, motility and proliferation is yet to be studied. This thesis therefore utilised a novel DUSP4 gene knockout mouse and investigated the effect of cellular MKP-2 removal in bone marrow derived macrophage (BMDMs) using a number of approaches.Results obtained from macrophage characterisation experiments demonstrated that following LPS stimulation MKP-2 deleted BMDMs showed enhanced JNK activation as opposed to other MAPKs, this effect was found to correlate with enhanced endothelin-1 (EDN1) expression at both gene and protein synthesis level. This is the first study to reveal that EDN1 expression is negatively regulated by MKP-2. MKP-2 deletion also resulted in different kinetic profiles for phagocytosis and migration which was also differed in M1 and M2 stimulated cultures. MKP-2-/- macrophages showed more phagocytic activity but less motility upon LPS activation, this effect was reversed when cells were pre-treated with IL-4 which gave less phagocytic activity but more motility. Also MKP-2 deletion reduced macrophage migration towards C5a suggesting a new role for MKP-2 gene in regulating macrophage motility.
Abstract Loss of MKP-2 also resulted in decreased macrophage proliferation activity.Finally, a metabolomics profile was established for both MKP-2+/+ and MKP-2-/- macrophages stimulated by different agents. MKP-2 deletion resulted in enhanced production of metabolites associated with glycolysis and the pentose phosphate pathway during the time at which MAPKs were upregulated indicative of a tight correlation between signalling and metabolic changes that underlie macrophage functions. In contrast, the proline and arginine pathway was downregulated in MKP-2 deleted macrophages. This was confirmed by studying nitric oxide production which was downregulated in MKP-2-/- macrophages upon LPS challenge which further correlated with changes in citrulline and ornithine. Collectively, this is the first study to investigate and determine the role of MKP-2 gene in macrophage functions; deletion or inhibition of MKP-2 in macrophages may be a therapeutically desirable approach.
Publication date 2018.
Name Plevin, Robin degree supervisor.
Name Paul, Andrew degree supervisor.
Name University of Strathclyde. Strathclyde Institute of Pharmacy and Biomedical Sciences.
Thesis note Thesis Ph. D. University of Strathclyde 2018 T15108
System Number 000005509

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