Down-regulation of neutrophil functions by the ELR(+) CXC chemokine platelet basic protein.
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.
Ehlert
J E
JE
Department of Immunology and Cell Biology and the Division of Biophysics, Forschungszentrum Borstel, Borstel, Germany.
Ludwig
A
A
Grimm
T A
TA
Lindner
B
B
Flad
H D
HD
Brandt
E
E
D000595:Amino Acid Sequence; D001779:Blood Coagulation Factors / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*; D001792:Blood Platelets / Q000502:physiology*; D019743:Chemokines, CXC / Q000097:blood*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008969:Molecular Sequence Data; D018375:Neutrophil Activation / Q000187:drug effects / Q000502:physiology*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000737:chemistry; D010455:Peptides / Q000097:blood* / Q000737:chemistry; D020033:Protein Isoforms / Q000737:chemistry / Q000502:physiology; D001620:beta-Thromboglobulin
D001779:Blood Coagulation Factors; D019743:Chemokines, CXC; C061615:PPBP protein, human; D010446:Peptide Fragments; D010455:Peptides; D020033:Protein Isoforms; D001620:beta-Thromboglobulin; C009862:connective tissue-activating peptide; C018329:low affinity platelet factor 4