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
- 15 March 2006
- journal article
- Published by American Society of Hematology in Blood
- Vol. 107 (6), 2234-2242
- https://doi.org/10.1182/blood-2005-06-2424
Abstract
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.Keywords
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