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Department of Immunology and Cell Biology, Forschungszentrum Borstel, Borstel, Germany
The neutrophil agonist neutrophil-activating peptide-2 (NAP-2) arises through proteolytic processing of platelet-derived N-terminally extended inactive precursors, the most abundant one being connective tissue-activating peptide-III (CTAP-III). Apart from N-terminal processing, C-terminal processing also appears to participate in the functional regulation of NAP-2, as indicated by our recent identification of an isoform missing four C-terminal amino acids, NAP-2 (1–66), which was about threefold more potent than full-size NAP-2. In the present study, we report on the discovery and identification of natural NAP-2 (1–63), an isoform truncated by seven C-terminal residues. Functional and receptor-binding analyses demonstrated that NAP-2 (1–63) represents the most active isoform, being about fivefold more potent than full-size NAP-2. Analyses of rNAP-2 isoforms successively truncated at the C terminus by up to eight residues suggest functionally important roles for acidic residues and for the leucine at position 63, a residue highly conserved within CXC chemokines. Finally, we report on a novel C-terminally truncated isoform of CTAP-III (CTAP-III (1–81)) representing the potential precursor of NAP-2 (1–66). We show that C-terminal truncation in CTAP-III enhances its potency to desensitize chemokine-induced neutrophil activation, indicating that C-terminal processing might not only serve to enhance neutrophil activation, but might as well participate in the down-regulation of an inflammatory response.
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