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The role of arachidonic acid mobilisation in myeloid cells

Mollapour, Elahe; (1999) The role of arachidonic acid mobilisation in myeloid cells. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Haemopoietic growth factors (GF) are important for regulating the proliferation and differentiation of immature cells, but granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 3 (IL-3) also have a role in regulating the function of mature phagocytic cells. The study presented in this thesis investigated the GF regulation of phospholipase A2 (PLA2) in immature and mature haemopoietic cells. In mature neutrophils, respiratory burst (NADPH oxidase) and PLA2 activity stimulated by the agonist FMLP can be enhanced (primed) by GF. A comparison was made between the mechanism of priming of both PLA2 and NADPH oxidase by GM-CSF and TNF. GM-CSF and TNF both stimulate the phosphorylation and activation of p42ERK2 and p38 MAP kinase (MAPK) in neutrophils. To investigate the role of these MAPKs in priming PLA2 and NADPH oxidase, inhibitors of p42ERK2 (PD098059) and p38 MAPK (SB203580) were used. Inhibition of p42ERK2 blocked neither superoxide generation nor cytokine-mediated priming, but partially inhibited cytokine-mediated priming of PLA2. In contrast inhibition of p38 MAPK blocked primed and unprimed NADPH oxidase activity, but only partially inhibited primed PLA2 activity. The dissociation of the priming of these two enzymes systems indicates that they may activated by different mechanisms. Inflammation of the vascular endothelium is pail of the pathogenic process in the crisis phase of sickle cell disease (SCD). This study investigated whether the priming of neutrophil PLA2 and NADPH oxidase activity in response to in vitro GM-CSF and TNF was altered in both the steady state and crisis of SCD. The data showed raised resting levels of neutrophil PLA2 even in the steady state, indicating an ongoing activation of these cells. But there were reduced responses of PLA2 and NADPH oxidase to GF priming in both steady state and crisis, and this may contribute to the susceptibility of these patients to infection. Immature cells were also studied. A range of myeloid and lymphocytic cell lines were screened for the presence of PLA2 activity measured by arachidonate release stimulated by calcium ionophore. Immature myeloid cells (HL-60 and K562) had extremely low PLA2 activity which was not enhanced by GF. Immature lymphocytic cells. Daudi and IL-2-dependent CTLL cells also released little arachidonic acid, and PLA2 activity was not further enhanced by stimulation with IL-2. However, the GF dependent myeloid cell lines (TF-1, THP-1) and purified human CD34+ stem cells showed higher levels of PLA2 activity which was increased by GM-CSF and IL-3. This suggests that PLA2 activity may be important for mediating the effects of myeloid growth factors.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The role of arachidonic acid mobilisation in myeloid cells
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Phospholipase A2
URI: https://discovery.ucl.ac.uk/id/eprint/10098383
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