title: The serpin-enzyme complex (SEC) receptor mediates the neutrophil chemotactic effect of alpha-1 antitrypsin-elastase complexes and amyloid-beta peptide.
abstract: The serpin-enzyme complex (SEC) receptor mediates catabolism of alpha 1-antitrypsin (alpha 1-AT)-elastase complexes and increases in synthesis of alpha 1-AT in cell culture. The SEC receptor recognizes a pentapeptide domain on alpha 1-AT-elastase complexes (alpha 1-AT 370-374), and the same domain in several other serpins, amyloid-beta peptide, substance P, and other tachykinins. Thus, it has also been implicated in the biological properties of these ligands, including the neurotoxic effect of amyloid-beta peptide. In this study, we examined the possibility that the SEC receptor mediates the previously described neutrophil chemotactic activity of alpha 1-AT-elastase complexes, and whether the other ligands for the SEC receptor have neutrophil chemotactic activity. The results show that 125I-peptide 105Y (based on alpha 1-AT 359-374) binds specifically and saturably to human neutrophils, and the characteristics of this binding are almost identical to that of monocytes and hepatoma-derived hepatocytes. Peptide 105Y and amyloid-beta peptide mediate chemotaxis for neutrophils with maximal stimulation at 1-10 nM. Mutant or deleted forms of peptide 105Y, which do not bind to the SEC receptor, have no effect. The neutrophil chemotactic effect of alpha 1-AT-elastase complexes is blocked by antiserum to peptide 105Y and by antiserum to the SEC receptor, but not by control antiserum. Preincubation of neutrophils with peptide 105Y or substance P completely blocks the chemotactic activity of amyloid-beta peptide, but not that of FMLP. These results, therefore, indicate that the SEC receptor can be modulated by homologous desensitization and raise the possibility that pharmacological manipulation of this receptor will modify the local tissue response to inflammation/injury and the neuropathologic reaction of Alzheimer's disease.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: G
authors.initials: G
authors.lastname: Joslin
authors.forename: G L
authors.initials: GL
authors.lastname: Griffin
authors.forename: A M
authors.initials: AM
authors.lastname: August
authors.forename: S
authors.initials: S
authors.lastname: Adams
authors.forename: R J
authors.initials: RJ
authors.lastname: Fallon
authors.forename: R M
authors.initials: RM
authors.lastname: Senior
authors.forename: D H
authors.initials: DH
authors.lastname: Perlmutter
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D002478:Cells, Cultured; D002630:Chemotactic Factors / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D006801:Humans; D019272:Leukocyte Elastase; D008969:Molecular Sequence Data; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D010196:Pancreatic Elastase / Q000378:metabolism / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000032:analysis / Q000502:physiology*; D000515:alpha 1-Antitrypsin / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D002630:Chemotactic Factors; D011956:Receptors, Cell Surface; D000515:alpha 1-Antitrypsin; C064184:serpin-enzyme complex receptor; D009240:N-Formylmethionine Leucyl-Phenylalanine; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase