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Human neutrophils express the alpha 1-antitrypsin gene and produce alpha
1-antitrypsin
RM du Bois, JF Bernaudin, P Paakko, R Hubbard, H Takahashi, V Ferrans and RG Crystal
Pulmonary Branch, National Heart, Lung, and Blood Institute, National
Institutes of Health, Bethesda, MD 20892.
The potent serine protease, neutrophil elastase (NE), is stored in
neutrophil azurophilic granules, where it is available to degrade
phagocytosed material and can be released by the cell to assist in tissue
migration and help clear tissue debris. While neutrophils carry NE, they
cannot produce it; the NE gene is expressed only in bone marrow granulocyte
precursor cells. Protection of normal tissues from the destructive capacity
of NE is provided by alpha 1-antitrypsin (alpha 1 AT), a 52-Kd serine
antiprotease produced by hepatocytes and mononuclear phagocytes. In the
context of the broad destructive capacity of NE, we evaluated the concept
that human neutrophils may be able to modulate the extracellular activity
of NE by synthesizing and secreting alpha 1AT. Immunocytochemical analysis
demonstrated that the neutrophil contains alpha 1AT. Northern analysis and
in situ hybridization with alpha 1AT-specific probes demonstrated the
presence of alpha 1AT messenger RNA transcripts within neutrophils.
[35S]methionine-labeling of neutrophils followed by immunoprecipitation of
the supernatant with an anti-alpha 1AT antibody and sodium dodecyl
sulfate-acrylamide gel analysis demonstrated that neutrophils can
synthesize alpha 1AT de novo and secrete the synthesized molecule. In the
presence of major neutrophil degranulation, the antiprotease effect of
neutrophil alpha 1AT is overwhelmed, allowing the NE to act unopposed in
the extracellular microenvironment. However, in conditions where small
amounts of NE are released by neutrophils, at least some of the secreted
newly synthesized alpha 1AT was capable of complexing with NE. Thus,
despite the fact that the neutrophil cannot synthesize NE, it can
synthesize and secrete alpha 1AT, the inhibitor of NE, ie, the neutrophil
is capable, to some extent, of modulating NE activity in the local milieu
without the help of antiproteases produced by other cells.
Volume 77,
Issue 12,
pp. 2724-2730,
06/15/1991
Copyright © 1991 by The American Society of Hematology
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