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Blood, 1 September 2002, Vol. 100, No. 5, pp. 1869-1877
PHAGOCYTES
Essential role of the C5a receptor in E coli-induced
oxidative burst and phagocytosis revealed by a novel lepirudin-based
human whole blood model of inflammation
Tom Eirik Mollnes,
Ole-Lars Brekke,
Michael Fung,
Hilde Fure,
Dorte Christiansen,
Grethe Bergseth,
Vibeke Videm,
Knut Tore Lappegård,
Jörg Köhl, and
John D. Lambris
From the Institute of Immunology, The National
Hospital, University of Oslo, Norway; Department of Immunology and
Transfusion Medicine, Department of Clinical Chemistry, and Medical
Department, Nordland Central Hospital and University of Tromsø;
Department of Immunology and Transfusion Medicine, Institute of
Laboratory Medicine, Norwegian University of Science and Technology,
Trondheim, Norway; Institute of Medical Microbiology, Medical School,
Hannover, Germany; Tanox, Houston, TX; and Laboratory of Protein
Chemistry, Department of Pathology and Laboratory Medicine, University
of Pennsylvania, PA.
Complement plays an essential role in inflammation and tissue
damage. However, it is largely unknown to what extent the system acts
as a primary inducer of secondary mediator systems in the inflammatory
network of human whole blood. Here we describe a novel in vitro model
using the thrombin-specific hirudin analog lepirudin as anticoagulant,
which, in contrast to heparin, did not interfere with complement
activation. The model was used to study the role of complement in
Escherichia coli-induced inflammatory responses.
Granulocyte and monocyte oxidative burst was complement dependent as it
was reduced by 85% and 70%, respectively, by the CD3 binding peptide
compstatin. A similar reduction was found by inhibition of C5, C5a, and
C5a receptor (C5aR). Furthermore, anti-CR3 antibodies were as efficient
as the C5aR antagonist in reducing granulocyte oxidative burst, whereas
blocking CD14 or C3aR had no effect. Up-regulation of granulocyte CR3
was virtually abolished by a C5aR antagonist. Opsonization and
phagocytosis was completely inhibited by blocking of C5aR or CR3,
whereas blocking of the Fc Rs (CD16, CD32, CD64) had no effect. In
contrast to oxidative burst and phagocytosis, cytokine secretion was
largely complement independent. Thus, anti-CD14 abolished tumor
necrosis factor- , interleukin-6 (IL-6), and IL-10 secretion, whereas
IL-8 was equally inhibited by anti-CD14 and compstatin. In conclusion, the present model is particularly useful for studying complement as
part of the inflammatory network. The results emphasize a crucial role
for C5a-C5aR interaction in E coli-induced up-regulation of CR3 and the subsequent oxidative burst and phagocytosis. Complement inhibition may have therapeutic implications in oxidative
burst-induced tissue damage.
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