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Title: Novel roles for elafin in the innate immune response
Author: McMichael, Jonathan William
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2004
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Several biochemical characteristics of elafin, such as low molecular weight, cationicity, heavy disulphide bonding and tissue distribution of mucosal sites, suggested that it may possess such-endotoxin properties similar to the defensins and other cationic antimicrobial peptides. Here we have demonstrated that elafin binds directly to LPS of both smooth-form and rough-form type. This bindings was shown to occur within the conserved lipid. A portion of the LPS molecule, and binding of elafin to LPS inhibited subsequent interaction of LPS with LPS-binding protein (LBP). Moreover, both terminal domains of elafin were shown to bind LPS and preclude this interaction. Furthermore, elafin inhibited TNF-α secretion in serum-free milieu. These findings suggest that extracellular elafin may play divergent roles in the innate immune response to LPS depending on the site of infection, for example serum-rich bloodstream or serum-deficient mucosal sites. A replication-deficient adenovirus vector encoding human elafin cDNA (Ad-elafin) was used to extend these studies to demonstrate that elafin may also act intracellularly to dampen macrophage responses to LPS. This LPS-modulatory activity prompted us to study the antimicrobial properties of elafin. Ad-elafin infection of primary murine tracheal epithelial cells ex vivo conferred antimicrobial activity against staphylococcus aureus, but compromised the inherent ability of cells to kill Pseudomonas aeruginosa. In summary, elafin may play a role in innate immunity by modulating host responses to Gram-negative bacterial LPS. Elafin could function to enhance immune responses in sites of local inflammation, such as the airways, but to down-regulate potentially deleterious responses to LPS in the circulation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available