Joslin G, Griffin G L, August A M, Adams S, Fallon R J, Senior R M, Perlmutter D H
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110.
J Clin Invest. 1992 Sep;90(3):1150-4. doi: 10.1172/JCI115934.
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.
丝氨酸蛋白酶抑制因子 - 酶复合物（SEC）受体介导α1 - 抗胰蛋白酶（α1 - AT）- 弹性蛋白酶复合物的分解代谢，并在细胞培养中增加α1 - AT的合成。SEC受体识别α1 - AT - 弹性蛋白酶复合物（α1 - AT 370 - 374）上的一个五肽结构域，以及其他几种丝氨酸蛋白酶抑制因子、β淀粉样肽、P物质和其他速激肽中的相同结构域。因此，它也与这些配体的生物学特性有关，包括β淀粉样肽的神经毒性作用。在本研究中，我们研究了SEC受体是否介导先前描述的α1 - AT - 弹性蛋白酶复合物的中性粒细胞趋化活性，以及SEC受体的其他配体是否具有中性粒细胞趋化活性。结果表明，125I - 肽105Y（基于α1 - AT 359 - 374）与人中性粒细胞特异性且饱和性结合，这种结合的特征与单核细胞和肝癌来源的肝细胞几乎相同。肽105Y和β淀粉样肽介导中性粒细胞的趋化作用，在1 - 10 nM时刺激作用最大。不与SEC受体结合的肽105Y突变体或缺失形式没有作用。α1 - AT - 弹性蛋白酶复合物的中性粒细胞趋化作用被抗肽105Y抗血清和抗SEC受体抗血清阻断，但不被对照抗血清阻断。用肽105Y或P物质预孵育中性粒细胞可完全阻断β淀粉样肽的趋化活性，但不阻断FMLP的趋化活性。因此，这些结果表明SEC受体可通过同源脱敏进行调节，并增加了通过药物操纵该受体将改变局部组织对炎症/损伤的反应以及阿尔茨海默病神经病理反应的可能性。
