A POTENT INHIBITOR OF ENDOTHELIAL-CELL PROLIFERATION IS GENERATED BY PROTEOLYTIC CLEAVAGE OF THE CHEMOKINE PLATELET FACTOR-4

Platelet factor 4 (PF-4) is an archetype of the ''chemokine'' family of low molecular weight proteins that play an important role in injury responses and inflammation, From activated human leukocyte culture supernatants, we have isolated a form of PF-4 that acts as a potent inhibitor of endothelial cell proliferation. The PF-4 derivative is generated by peptide bond cleavage between Thr-16 and Ser-17, a site located downstream from the highly conserved and structurally important CXC motif. The unique cleavage leads to a loss of one of the structurally important large loops in the PF-4 molecule and generation of an N terminus with basic residues that have the potential to interact with the acidic extracellular domain of the G-protein-coupled chemokine receptor. The N-terminal processed PF-4 exhibited a 30- to 50-fold greater growth inhibitory activity on endothelial cells than PF-4, Since endothelial cell growth inhibition is the only known cellular activity of the cleaved PF 4, we have designated this chemokine endothelial cell growth inhibitor. The N-terminal processing of PF-4 may represent an important mechanism for modulating PF 4 activity on endothelial cells during tissue injury, inflammation, and neoplasia.