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Blood, 1 November 2000, Vol. 96, No. 9, pp. 2965-2972
CHEMOKINES
Down-regulation of neutrophil functions by the ELR+
CXC chemokine platelet basic protein
Jan E. Ehlert,
Andreas Ludwig,
Tobias A. Grimm,
Buko Lindner,
Hans-Dieter Flad, and
Ernst Brandt
From the Department of Immunology and Cell Biology and
the Division of Biophysics, Forschungszentrum Borstel, Borstel,
Germany.
The platelet-derived neutrophil-activating peptide 2 (NAP-2,
70 amino acids) belongs to the ELR+ CXC subfamily of
chemokines. Similar to other members of this group, such as IL-8, NAP-2
activates chemotaxis and degranulation in neutrophils
(polymorphonuclear [PMN]) through chemokine receptors CXCR-1 and
CXCR-2. However, platelets do not secrete NAP-2 as an active chemokine
but as the C-terminal part of several precursors that lack
PMN-stimulating capacity. As we have previously shown, PMN themselves
may liberate NAP-2 from the precursor connective tissue-activating
peptide III (CTAP-III, 85 amino acids) by proteolysis. Instead of
inducing cell activation, continuous accumulation of the chemokine in
the surroundings of the processing cells results in the down-regulation
of specific surface-expressed NAP-2 binding sites and in the
desensitization of chemokine-induced PMN degranulation. Thus, NAP-2
precursors may be regarded as indirect mediators of functional
desensitization in neutrophils. In the current study we investigated
the biologic impact of another major NAP-2 precursor, the platelet
basic protein (PBP, 94 amino acids). We show that PBP is considerably
more potent than CTAP-III to desensitize degranulation and chemotaxis
in neutrophils. We present data suggesting that the high desensitizing
capacity of PBP is based on its enhanced proteolytic cleavage into
NAP-2 by neutrophil-expressed cathepsin G and that it involves
efficient down-regulation of surface-expressed CXCR-2 while CXCR-1 is
hardly affected. Correspondingly, we found PBP and, less potently,
CTAP-III to inhibit CXCR-2- but not CXCR-1- dependent chemotaxis of
neutrophils toward NAP-2. Altogether our findings demonstrate that the
anti-inflammatory capacity of NAP-2 is governed by the species of its precursors.
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