Regulation of P-selectin binding to the neutrophil P-selectin counter-receptor P-selectin glycoprotein ligand-1 by neutrophil elastase and cathepsin G
Department of Pediatrics
Medical Subject Headings
Amino Acid Sequence; Autocrine Communication; Cathepsin G; Cathepsins; Humans; Inflammation; Leukocyte Elastase; Membrane Glycoproteins; Metalloendopeptidases; Molecular Sequence Data; Neutrophils; P-Selectin; Platelet Glycoprotein GPIb-IX Complex; Protein Binding; Serine Endopeptidases
Hematology | Oncology | Pediatrics
In the inflammatory response, leukocyte rolling before adhesion and transmigration through the blood vessel wall is mediated by specific cell surface adhesion receptors. Neutrophil rolling involves the interaction of P-selectin expressed on activated endothelium and its counter-receptor on neutrophils, P-selectin glycoprotein ligand-1 (PSGL-1). Here, it is reported that P-selectin binding to neutrophils is lost under conditions that cause the release of proteinases from neutrophil primary granules. Treatment of neutrophils with the purified neutrophil granule proteinases, cathepsin G and elastase, rapidly abolished their capacity to bind P-selectin. This inactivation corresponded to loss of the N-terminal domain of PSGL-1, as assessed by Western blot analysis. A loss of intact PSGL-1 protein from the surfaces of neutrophils after the induction of degranulation was also detected by Western blot analysis. Cathepsin G initially cleaved near the PSGL-1 N-terminus, whereas neutrophil elastase predominantly cleaved at a more C-terminal site within the protein mucin core. Consistent with this, cathepsin G cleaved a synthetic peptide based on the PSGL-1 N-terminus between Tyr-7/Leu-8. Under conditions producing neutrophil degranulation in incubations containing mixtures of platelets and neutrophils, the loss of PSGL-1, but not P-selectin, from platelet-neutrophil lysates was detected. Cathepsin G- or neutrophil elastase-mediated PSGL-1 proteolysis may constitute a potential autocrine mechanism for down-regulation of neutrophil adhesion to P-selectin.
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Citation: Blood. 2001 Sep 1;98(5):1440-7. doi 10.1182/blood.V98.5.1440
Gardiner, Elizabeth E.; De Luca, Mariagrazia; McNally, Tracy; Michelson, Alan D.; Andrews, Robert K.; and Berndt, Michael C., "Regulation of P-selectin binding to the neutrophil P-selectin counter-receptor P-selectin glycoprotein ligand-1 by neutrophil elastase and cathepsin G" (2001). Hematology/Oncology. 32.