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Prepublished online as a Blood First Edition Paper on October 17, 2002; DOI 10.1182/blood-2002-06-1734.
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Blood, 1 March 2003, Vol. 101, No. 5, pp. 1752-1758
HEMATOPOIESIS
Neutrophil elastase enzymatically antagonizes the in vitro action
of G-CSF: implications for the regulation of granulopoiesis
Frank El Ouriaghli,
Hiroshi Fujiwara,
J. Joseph Melenhorst,
Giuseppe Sconocchia,
Nancy Hensel, and
A. John Barrett
From the Hematology Branch, National Heart, Lung and
Blood Institute, National Institutes of Health, Bethesda, MD.
There is evidence that neutrophil production is a balance between
the proliferative action of granulocyte-colony-stimulating factor
(G-CSF) and a negative feedback from mature neutrophils (the chalone).
Two neutrophil serine proteases have been implicated in granulopoietic
regulation: pro-proteinase 3 inhibits granulocyte macrophage-colony-forming unit (CFU-GM) growth, and elastase mutations cause cyclic and congenital neutropenia. We further studied the action
of the neutrophil serine proteases (proteinase 3, elastase, azurocidin,
and cathepsin G) on granulopoiesis in vitro. Elastase inhibited CFU-GM
in methylcellulose culture. In serum-free suspension cultures of
CD34+ cells, elastase completely abrogated the
proliferation induced by G-CSF but not that of GM-CSF or stem cell
factor (SCF). The blocking effect of elastase was prevented by
inhibition of its enzymatic activity with phenylmethylsulfonyl fluoride
(PMSF) or heat treatment. When exposed to enzymatically active
elastase, G-CSF, but not GM-CSF or SCF, was rapidly cleaved and
rendered inactive. These results support a role for neutrophil elastase in providing negative feedback to granulopoiesis by direct antagonism of G-CSF.
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