Activated neutrophils secrete stored α1-antitrypsin

P. Paakko, M. Kirby, R. M. Du Bois, A. Gillissen, V. J. Ferrans, R. G. Crystal

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Abstract

Neutrophil elastase (NE), a potent serine protease, is stored in primary granules of neutrophils and released following neutrophil activation. Alpha-1-antitrypsin (α1-AT), the major inhibitor of NE, is synthesized by mature neutrophils. In the context of the maintenance of tissue homeostasis, we hypothesized that neutrophils may be able to store α1-AT, thus having it available for release concordantly with NE. Immunofluorescence and quantitative flow-cytometric studies of neutrophils and monocytes labeled with fluorescein-conjugated α1-AT-antibody demonstrated larger amounts of cytoplasmic α1-AT in neutrophils than in monocytes. [35S]methionine-labeling and anti-α1-AT immunoprecipitation analysis showed that although both neutrophils and monocytes synthesize α1-AT, the proportion of newly synthesized intracellular α1-AT was much higher in neutrophils than in monocytes. Flow-cytometric analysis showed that in the presence of surface stimulation with cytochalasin B followed by formyl-methionyleucylphenylalanine (fMLP), mean intracellular α1-AT was decreased in stimulated neutrophils compared with that in resting cells, suggesting that the stored α1-AT was rapidly released following surface triggering. Evaluation of surface-stimulated neutrophils by [35S]methionine labeling and anti-α1-AT immunoprecipitation demonstrated increased secretion of α1-AT compared with that of resting neutrophils, with some of the secreted α1-AT capable of forming complexes with NE. Thus, neutrophils respond to surface stimulation not only by secreting NE but also by secreting its inhibitor, α1-AT, suggesting that these cells have an inherent mechanism for damping the local effects of NE, their most powerful proteolytic enzyme.

Original languageEnglish
Pages (from-to)1829-1833
Number of pages5
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume154
Issue number6
DOIs
Publication statusPublished - 1 Jan 1996

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ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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