Lactoferrin inhibits the lipopolysaccharide-induced expression and proteoglycan-binding ability of interleukin-8 in human endothelial cells.
Interleukin-8 (IL-8), a C-X-C chemokine bound to endothelium proteoglycans, initiates the activation and selective recruitment of leukocytes at inflammatory foci. We demonstrate that human lactoferrin, an antimicrobial lipopolysaccharide (LPS)-binding protein, decreases both IL-8 mRNA and protein expression induced by the complex Escherichia coli 055:B5 LPS/sCD14 in human umbilical vein endothelial cells. The use of recombinant lactoferrins mutated in the LPS-binding sites indicates that this inhibitory effect is mediated by an interaction of lactoferrin with LPS and CD14s that suppresses the endotoxin biological activity. Furthermore, since dimeric IL-8 and lactoferrin are both proteoglycan-binding molecules, the competition between these proteins for heparin binding was investigated. Lactoferrin strongly inhibited the interaction of radiolabeled IL-8 to immobilized heparin, whereas a lactoferrin variant lacking the amino acid residues essential for heparin binding was not inhibitory. Moreover, this process is specific, since serum transferrin, a glycoprotein whose structure is close to that of lactoferrin, did not prevent the interaction of IL-8 with heparin. These results suggest that the anti-inflammatory properties of lactoferrin during septicemia are related, at least in part, to the regulation of IL-8 production and also to the ability of lactoferrin to compete with chemokines for their binding to proteoglycans.
Elass
Elisabeth
E
Laboratoire de Chimie Biologique et Unité Mixte de Recherche no. 8576 du Centre National de la Recherche Scientifique, Université des Sciences et Technologies de Lille, 59655 Villeneuve d'Ascq cedex, France. Elisabeth.Elass@univ-lille1.fr
Masson
Maryse
M
Mazurier
Joël
J
Legrand
Dominique
D
D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D007781:Lactoferrin / Q000494:pharmacology*; D018950:Lipopolysaccharide Receptors / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D011509:Proteoglycans / Q000378:metabolism*
D016209:Interleukin-8; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D011509:Proteoglycans; D006493:Heparin; D007781:Lactoferrin