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Title: The pro-inflammatory role of copper in chemokine multimerisation and the potential of copper chelators as anti-inflammatory agents
Author: MacGregor, Helen Jane
ISNI:       0000 0004 2673 4918
Awarding Body: University of Portsmouth
Current Institution: University of Portsmouth
Date of Award: 2009
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Since both copper and dityrosine links have been implicated in the multimerisation of the amyloid protein in Alzheimer's disease, chemokines including RANTES, IL-8 and ENA-78 were investigated for the possibility of copper-induced dityrosine formation within chemokine multimers. The addition of CuCl₂ and H₂O₂ to human recombinant RANTES induces multimerisation and dityrosine cross-linking, confirmed by fluorimetry, liquid chromatography mass spectroscopy and staining Western blots with a dityrosine specific monoclonal antibody. In addition, RANTES multimers actively induce chemotaxis in Boyden chambers. This finding led to the investigation of the T-cell response to endothelial and platelet derived RANTES in the absence and presence of copper chelators as potential anti-inflammatory agents in transendothelial migration assays, a physiological model of the vascular endothelium. Migration of activated T-cells across monolayers of human lung microvascular endothelial cells was RANTES-dependent and RANTES derived from thrombin stimulated platelets is active as a T-cell chemoattractant in this model of the lung microvascular endothelium. The copper chelators neocuprine, bathocuproine, D-penicillamine and tobramycin significantly inhibited T-cell migration indicating a pro-inflammatory role for copper and suggesting the use of copper chelators as potential anti-inflammatory agents.
Supervisor: Shute, Janis Kay Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available