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 <i>ex vivo </i>conferred antimicrobial activity against <i>staphylococcus aureus, </i>but compromised the inherent ability of cells to kill <i>Pseudomonas aeruginosa. </i> 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.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:657075 |
| Date | January 2004 |
| Creators | McMichael, Jonathan William |
| Publisher | University of Edinburgh |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/1842/24961 |
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