Do native and polymeric alpha1-antitrypsin activate human neutrophils in vitro?

Caroline Persson, Devipriya Subramaniyam, Tim Stevens, Sabina Janciauskiene

Research output: Contribution to journalArticlepeer-review

Abstract

Background: {alpha}1-Antitrypsin (AAT)-Z deficiency is a risk factor for the development of COPD. Compared to wild-type M, AAT-Z has an increased tendency to polymerize, rendering it inactive as a serine proteinase inhibitor. It has been demonstrated that wild-type M- and Z-deficiency AAT polymers are chemotactic for human neutrophils. However, our own studies dispute a proinflammatory role for polymerized AAT-M and AAT-Z, suggesting rather that they are predominantly antiinflammatory, exhibiting inhibitory effects on lipopolysaccharide-stimulated human monocyte activation. The discrepancies between these observations prompted us to re-examine the effects of AAT.

Methods and results: The effects of native and polymerized AAT-M and AAT-Z with varying levels of endotoxin contamination (0.08 to 2.55 endotoxin units [EU]/mg protein) on human neutrophil chemotaxis and interleukin (IL)-8 release, in vitro, were evaluated. Neither native nor polymerized (M- or Z-deficient) AAT contaminated with low levels of endotoxin (≤ 0.08 EU/mg protein) stimulated neutrophil chemotaxis, whereas N-formyl methionyl leucyl phenylalanine (fMLP), a positive control, increased chemotaxis fourfold. A small but nonsignificant increase in neutrophil chemotaxis, however, was observed with AAT preparations containing higher levels of endotoxin (≥ 0.88 EU/mg protein), and significant chemotaxis occurred when AAT was spiked with either endotoxin or zymosan. In support, native and polymeric AAT-M with low endotoxin contamination completely inhibited neutrophil IL-8 release triggered by the zymosan, while AATs with high endotoxin contamination strongly induced IL-8 release and did not inhibit zymosan-stimulated IL-8 release.

Conclusions: The proinflammatory effects of native and polymeric AAT may be critically dependent on the presence of other cell activators, bacterial or otherwise, while pure preparations of AAT appear to exert predominantly antiinflammatory activity.
Original languageEnglish
Pages (from-to)1683-1692
JournalChest
Volume129
Issue number6
Publication statusPublished - 2006

Bibliographical note

The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Chronic Inflammatory and Degenerative Diseases Research Unit (013242530), Emergency medicine/Medicine/Surgery (013240200)

Subject classification (UKÄ)

  • Respiratory Medicine and Allergy

Keywords

  • {alpha}1-antitrypsin • chemotaxis • endotoxin • neutrophils • polymers

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