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Blood, Vol. 93 No. 3 (February 1), 1999:
pp. 849-856
A Secreted Proform of Neutrophil Proteinase 3 Regulates the
Proliferation of Granulopoietic Progenitor Cells
Stefan Sköld,
Bodil Rosberg,
Urban Gullberg, and
Tor Olofsson
From the Department of Hematology, Research Department 2, University
Hospital, Lund, Sweden.
Myeloid leukemia cells, the human promyelocytic cell line HL-60, and
a subpopulation of normal marrow cells produce a leukemia-associated inhibitor (LAI) that reversibly downmodulates DNA synthesis of normal
granulopoietic progenitor cells colony-forming unit
granulocyte-macrophage (CFU-GM). We isolated an active 125-kD
component of LAI from HL-60 conditioned medium (CM), subjected it to
cyanogen bromide cleavage and show by amino acid
sequencing of the resulting peptides that it consists of a complex of
the serine proteinase inhibitor  1-antitrypsin and a 31-kD fragment
that retained the S-phase inhibitory activity, but resisted sequencing.
This finding suggested that the 31-kD fragment originated from one of
the neutrophil serine proteases (ie, elastase, proteinase 3, or
cathepsin G) produced by normal promyelocytes, as well as HL-60 cells,
for storage in primary granules and partly secreted during synthesis as
enzymatically inactive proforms. Immunoblot analysis showed that the
125-kD complex contained proteinase 3 (PR3), and immunoprecipitation of
PR3 from HL-60 CM abrogated the S-phase inhibitory activity, whereas immunoprecipitation of cathepsin G or elastase did not. Immunoprecipitation of PR3 from CM of a subpopulation of normal marrow
cells also abrogated the S-phase inhibitory effect. Furthermore, CM
from rat RBL and murine 32D cell lines transfected with human PR3 both
reduced the fraction of CFU-GM in S-phase with 30% to 80% at 1 to 35 ng/mL PR3, whereas CM of the same cells transfected with cathepsin G or
elastase did not. Also, an enzymatically silent mutant of PR3 exerted
full activity, showing that the S-phase modulatory effect is not
dependent on proteolytic activity. Amino acid sequencing of
biosynthetically radiolabeled PR3 showed that PR3 from transfected
cells is secreted after synthesis as proforms retaining amino terminal
propeptides. In contrast, mature PR3 extracted from mature neutrophils
has only minor activity. The inhibitory effect of secreted PR3 is
reversible and abrogated by granulocyte (G)- or granulocyte-macrophage
colony-stimulating factor (GM-CSF). Experiments with highly purified
CD34+ bone marrow cells suggested that PR3 acts directly
on the granulopoietic progenitor cells. These observations suggest a
role for PR3 in regulation of granulopoiesis, and possibly in
suppression of normal granulopoiesis in leukemia.
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