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Blood, 15 March 2006, Vol. 107, No. 6, pp. 2234-2242.
Prepublished online as a Blood First Edition Paper on November 29, 2005; DOI 10.1182/blood-2005-06-2424.
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Submitted June 17, 2005
Accepted October 25, 2005
Mast cells and neutrophils proteolytically activate chemokine precursor CTAP-III and are subject to counter-regulation by PF-4 through inhibition of chymase and cathepsin G
Florian Schiemann*, Tobias A Grimm, Josef Hoch, Roland Gross, Buko Lindner, Frank Petersen, Silvia Bulfone-Paus, and Ernst Brandt
Department of Immunology and Cell Biology, Forschungszentrum Borstel, Borstel, Germany
Clinic for hand-, breast- and plastic surgery, Klinikum Neustadt, Neustadt i.H., Germany
* Corresponding author; email: fschie{at}fz-borstel.de.
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 also activated human skin mast cells (MC) 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 MC exceed the CTAP-III processing potency of neutrophils about 30-fold, whereas MC 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 also cleavage of the CTAP-III-unrelated substrate substance P was 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.
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