Mast cells and neutrophils proteolytically activate chemokine precursor CTAP-III and are subject to counterregulation by PF-4 through inhibition of chymase and cathepsin G

• Published in: Blood Vol. 107; no. 6; pp. 2234 - 2242
• Main Authors: Schiemann, Florian, Grimm, Tobias Alexander, Hoch, Josef, Gross, Roland, Lindner, Buko, Petersen, Frank, Bulfone-Paus, Silvia, Brandt, Ernst
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.03.2006; The Americain Society of Hematology
• Subjects: Analysis of the immune response. Humoral and cellular immunity; Biological and medical sciences; Cathepsin G; Cathepsins - antagonists & inhibitors; Cathepsins - metabolism; Cell interactions; Chymases; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; Immunobiology; Immunoglobulin E - metabolism; Mast Cells - metabolism; N-Formylmethionine Leucyl-Phenylalanine - pharmacology; Neutrophils - metabolism; Nuclear Proteins - metabolism; Peptides - metabolism; Platelet Factor 4 - physiology; Serine Endopeptidases - metabolism; Serine Proteinase Inhibitors; Substance P - metabolism; Human; Connective tissue activating peptide III; Serine endopeptidases; Enzyme; Cathepsin G; Inflammation; Precursor; Neutrophil activating peptide 2; Chymase; Chemokine; Peptidases; Platelet factor 4; Regulation(control); Platelet; Immunology; Proteolysis; Hydrolases; Mast cell; Mediator; Neutrophil
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2005-06-2424

The CXC chemokines platelet factor 4 (PF-4/CXCL4) and connective tissue-activating peptide III (CTAP-III) are released by activated human platelets in micromolar concentrations. So far, neutrophils have been recognized to cleave the precursor CTAP-III to form the active chemokine neutrophil-activating peptide 2 (NAP-2/CXCL7) through limited proteolysis by membrane-associated cathepsin G. Here we show for the first time that activated human skin mast cells (MCs) convert CTAP-III into biologically active NAP-2 through proteolytic cleavage by released chymase. A direct comparison on a cell number basis revealed that unstimulated MCs exceed the CTAP-III–processing potency of neutrophils about 30-fold, whereas MCs activated by IgE cross-linking exhibit even 1000-fold higher CTAP-III–processing capacity than fMLP-stimulated neutrophils. Intriguingly, PF-4 counteracted MC- as well as neutrophil-mediated NAP-2 generation at physiologically relevant concentrations. Addressing the underlying mechanism, we obtained evidence that PF-4 acts as an inhibitor of the CTAP-III–processing enzymes cathepsin G and chymase without becoming cleaved itself as a competitive substrate. Because cleavage of the CTAP-III–unrelated substrate substance P was also affected by PF-4, our results suggest a regulatory role for PF-4 not only in NAP-2 generation but also in neutrophil- and MC-mediated processing of other physiologically relevant inflammatory mediators.