THE SERPIN-ENZYME COMPLEX (SEC) RECEPTOR MEDIATES THE NEUTROPHIL CHEMOTACTIC EFFECT OF BETA-1 ANTITRYPSIN-ELASTASE COMPLEXES AND AMYLOID-BETA PEPTIDE

被引:69
作者
JOSLIN, G
GRIFFIN, GL
AUGUST, AM
ADAMS, S
FALLON, RJ
SENIOR, RM
PERLMUTTER, DH
机构
[1] WASHINGTON UNIV,SCH MED,DEPT PEDIAT,400 S KINGSHIGHWAY BLVD,ST LOUIS,MO 63110
[2] UNIV WASHINGTON,JEWISH HOSP,MED CTR,DIV RESP BIOL SCI,SEATTLE,WA 98195
[3] MONSANTO CO,DEPT BIOL SCI,ST LOUIS,MO 63110
[4] UNIV WASHINGTON,CHILDRENS HOSP,MED CTR,DIV GASTROENTEROL & NUTR,SEATTLE,WA 98195
[5] UNIV WASHINGTON,CHILDRENS HOSP,MED CTR,DIV HEMATOL & ONCOL,SEATTLE,WA 98195
[6] WASHINGTON UNIV,SCH MED,DEPT CELL BIOL,ST LOUIS,MO 63110
[7] WASHINGTON UNIV,SCH MED,DEPT INTERNAL MED,ST LOUIS,MO 63110
[8] WASHINGTON UNIV,SCH MED,DEPT PHYSIOL,ST LOUIS,MO 63110
关键词
SERPINS; PROTEASE INHIBITORS; INFLAMMATION; ALZHEIMERS DISEASE; DOWNS SYNDROME;
D O I
10.1172/JCI115934
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 I-125-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.
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收藏
页码:1150 / 1154
页数:5
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