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Prepublished online as a Blood First Edition Paper on November 21, 2002; DOI 10.1182/blood-2002-07-2261.
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Blood, 1 April 2003, Vol. 101, No. 7, pp. 2810-2815
PHAGOCYTES
The heat shock protein Gp96 binds to human neutrophils and
monocytes and stimulates effector functions
Markus P. Radsak,
Norbert Hilf,
Harpreet Singh-Jasuja,
Sibylla Braedel,
Peter Brossart,
Hans-Georg Rammensee, and
Hansjoerg Schild
From the University Medical Hospital, Department
Hematology/Oncology, University of Tübingen, Tübingen,
Germany; and the Institute for Cell Biology, Department
Immunology, University of Tübingen, Tübingen,
Germany.
The endoplasmic reticulum (ER)-resident heat
shock protein Gp96 is involved in protein folding and is
released into the extracellular space after necrotic cell death. In
this context, Gp96 has immunostimulatory properties: it activates
dendritic cells or macrophages and delivers associated peptides into
the antigen presentation pathway, resulting in the induction of
specific T-cell responses. The inflammatory response after necrotic
tissue damage leads to the recruitment of polymorphonuclear neutrophils
(PMNs) and monocytes, allowing them to make their first encounter with
Gp96. We therefore investigated whether PMNs and monocytes interact
with Gp96. We were able to show that PMNs and monocytes specifically
bind fluorescein isothiocyanate (FITC)-conjugated Gp96. The
binding of Gp96-FITC was competed by lipopolysaccharide (LPS) or
fucoidan, a known inhibitor of scavenger receptors. Interestingly, the
binding of LPS-FITC was also competed not only by fucoidan, but by
Gp96, suggesting that LPS and Gp96 share a common receptor on PMNs. One
important effector function of PMNs is the clearance of an inflammatory
site by phagocytosis. We therefore assessed the influence of Gp96 on
phagocytic activity using fluorochrome-labeled polystyrene beads. We
found a marked enhancement of phagocytosis in the presence of Gp96 and
concluded that PMNs not only bind Gp96, but are also activated by
it. Additionally, Gp96-stimulated PMNs and especially monocytes
release large amounts of interleukin-8, a potent neutrophil-attracting
chemokine. In conclusion, we demonstrate that Gp96 specifically binds
to and activates PMNs and monocytes, extending the function of Gp96 as a danger signal to additional members of the innate immune system.
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