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C3a activates the respiratory burst in human polymorphonuclear neutrophilic
leukocytes via pertussis toxin-sensitive G-proteins
J Elsner, M Oppermann, W Czech and A Kapp
Department of Dermatology, University of Freiburg, Germany.
In contrast to C5a, which represents a well-established potent activator of
the respiratory burst in polymorphonuclear neutrophilic granulocytes (PMN),
the functional role of C3a in the activation of PMN is, so far, poorly
understood. Herein, the potential role of human C3a in the activation of
the respiratory burst in human PMN was investigated. The release of
reactive oxygen species (ROS) of PMN from healthy donors was measured by
lucigenin-dependent chemiluminescence. C3a dose-dependently induced the
production of ROS in human PMN in the range between 10 ng/mL and 1,000
ng/mL, whereas C3a-desArg was inactive. Flow cytometric measurement of H2O2
by dihydrorhodamine-123 labeling of anti-CD16-stained PMN showed that
predominantly neutrophilic PMN are responsible for the C3a-induced
activation of the respiratory burst. To exclude that C3a stimulation was
caused by contamination with C5a, the specificity of C3a-induced activation
of PMN was shown using monoclonal antibodies (MoAbs). Accordingly, the
effect of C3a was completely abolished in the presence of Fab fragments of
a blocking anti-C3a MoAb. In addition, blockade of the C5a receptor by the
anti-C5a receptor (anti-C5aR) MoAb, S5/1, totally inhibited the C5a-induced
production of ROS, whereas the C3a response in the presence of the
anti-C5aR MoAb was unaffected. The specificity of the response was further
confirmed by homologous desensitization after restimulation with C3a. In
contrast, no cross-desensitization was observed upon stimulation with C5a.
The C3a-induced ROS production by PMN was inhibited by pertussis toxin,
indicating the involvement of guanine nucleotide-binding proteins (Gi
proteins) in the signal transduction process initiated by C3a. In addition,
stimulation of PMN by C3a resulted in a transient increase in the cytosolic
free calcium concentration ([Ca2+]i) in a dose-dependent manner. In
contrast to C3a- induced ROS production, C3a did not induce a chemotactic
response in PMN, indicating functional qualitative differences as compared
with C5a. In summary, these results show that C3a is a potent activator of
the respiratory burst in human PMN. Therefore, these findings point to a
novel role of C3a in the pathogenesis of inflammatory diseases associated
with increased C3a levels and PMN activation.
Volume 83,
Issue 11,
pp. 3324-3331,
06/01/1994
Copyright © 1994 by The American Society of Hematology
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