title: Modulation of lipopolysaccharide-induced monocyte activation by heparin-binding protein and fucoidan.
abstract: Activated polymorphonuclear leukocytes release heparin-binding protein (HBP; also known as CAP37 or azurocidin) from azurophilic granules. HBP is a strong chemoattractant for monocytes that also prolongs monocyte survival and potentiates endotoxin (lipopolysaccharide [LPS])-induced production of tumor necrosis factor alpha (TNF-alpha). We investigated the binding of fluorescein isothiocyanate-conjugated HBP to human monocytes in the presence of EDTA and the polysaccharide fucoidan. EDTA, which chelates divalent cations, has been widely used to study the role of divalent cations in receptor-ligand interactions or enzyme activity. Fucoidan has been used to inhibit the binding of various ligands to scavenger receptors or selectins. Scavenger receptors are multiligand receptors that mediate endocytosis of proteases, protease-inhibitor complexes, lipoproteins, and LPS-lipid A. Fucoidan also interferes with leukocyte rolling by binding to L-selectins (expressed on leukocytes) and P-selectins (expressed on platelets and endothelium). We demonstrate that the binding of the neutrophil-derived protein HBP to monocytes is inhibited in the presence of EDTA and fucoidan. In addition, fucoidan and EDTA abrogate the enhancing effect of HBP on LPS-induced TNF-alpha production. These data provide supporting evidence that HBP binds to a receptor expressed on monocytes. This receptor is dependent on divalent cations and is possibly related to the scavenger receptor. Furthermore, we demonstrate that fucoidan, by itself, stimulates TNF-alpha release from isolated monocytes in a CD14-independent fashion. This is an important finding for the interpretation of results from studies that use fucoidan to "block" either scavenger receptors or L- or P-selectins.
authors.affiliation: Department of Physiology and Biophysics, Department of Surgery, University of Louisville, School of Medicine, Louisville, Kentucky, USA. mheinzelmann@bluewin.ch
authors.forename: M
authors.initials: M
authors.lastname: Heinzelmann
authors.forename: H C
authors.initials: HC
authors.lastname: Polk
authors.forename: F N
authors.initials: FN
authors.lastname: Miller
mesh_terms: D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins / Q000378:metabolism / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism / Q000494:pharmacology*; D004347:Drug Interactions; D004492:Edetic Acid / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D018945:Monocyte Chemoattractant Proteins / Q000378:metabolism / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects*; D009504:Neutrophils / Q000737:chemistry; D011134:Polysaccharides / Q000494:pharmacology*; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: C062991:AZU1 protein, human; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D002352:Carrier Proteins; D008024:Ligands; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D018945:Monocyte Chemoattractant Proteins; D011134:Polysaccharides; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; C116128:heparin-binding protein receptor; C007789:fucoidan; D004492:Edetic Acid