Connective tissue-activating peptide III desensitizes chemokine receptors on neutrophils. Requirement for proteolytic formation of the neutrophil-activating peptide 2.
The connective tissue-activating peptide III (CTAP-III), which is released from activated platelets, represents an inactive precursor of the chemokine neutrophil-activating peptide 2 (NAP-2). Leukocytes and leukocyte-derived proteases have been found to convert CTAP-III into NAP-2 by proteolytic cleavage at the N terminus. We demonstrate here that rapid and efficient formation of NAP-2 is mediated by neutrophil granulocytes (PMN) but not by monocytes or lymphocytes. However, as seen in a degranulation assay, neutrophils processing CTAP-III did not become activated by the generated NAP-2 and even exhibited decreased responsiveness to high doses of NAP-2 or IL-8, but not to FMLP. The desensitizing effect, being maximal already after 5 min of preincubation with CTAP-III, was not mediated through binding of the precursor to specific receptors but correlated with the rapid down-modulation of common NAP-2/IL-8 high affinity binding sites. A similar functional and receptor desensitization was observed in PMN pre-exposed to nonstimulatory doses of NAP-2. Specific inhibition of the CTAP-III-cleaving enzyme by the serine protease inhibitor aprotinin abrogated the CTAP-III, but not the NAP-2-mediated effects. Desensitization of PMN by CTAP-III was due to NAP-2 generated by proteolytic truncation of CTAP-III. Our results suggest that CTAP-III may regulate PMN activation by protecting processing cells from premature activation.
Härter
L
L
Department of Immunology and Cell Biology, Borstel Research Institute, Germany.
Petersen
F
F
Flad
H D
HD
Brandt
E
E
D001779:Blood Coagulation Factors / Q000378:metabolism / Q000502:physiology*; D015550:Cell Degranulation / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D019272:Leukocyte Elastase; D007963:Leukocytes, Mononuclear / Q000276:immunology; D009504:Neutrophils / Q000276:immunology*; D010196:Pancreatic Elastase / Q000097:blood; D010455:Peptides / Q000502:physiology*; D018121:Receptors, Cytokine / Q000378:metabolism*; D001620:beta-Thromboglobulin
D001779:Blood Coagulation Factors; D016209:Interleukin-8; C061615:PPBP protein, human; D010455:Peptides; D018121:Receptors, Cytokine; D001620:beta-Thromboglobulin; C009862:connective tissue-activating peptide; C018329:low affinity platelet factor 4; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase