Platelet factor 4 binds to interleukin 8 receptors and activates neutrophils when its N terminus is modified with Glu-Leu-Arg.
Amino acid deletion and mutagenesis experiments have indicated that the sequences Glu-Leu-Arg (ELR) preceding the first cysteine at the N terminus of interleukin 8 (IL-8) is required for receptor binding and neutrophil activation. Platelet factor 4 (PF4) is structurally related to IL-8 (35% sequence identity) but lacks the N-terminal ELR sequence and comparable effects on neutrophils. We introduced the ELR sequence at the N terminus of PF4 and found that the modified protein was a potent neutrophil activator and attractant. On the other hand, when the ELR sequence was introduced into the corresponding positions of two other proteins related to IL-8, gamma-interferon-inducible protein IP10 and monocyte chemoattractant protein 1, neither of them acquired neutrophil-activating properties, indicating that besides ELR additional structural determinants of IL-8 and PF4 are important for binding to IL-8 receptors. The conservation of these binding determinants suggests that PF4 may have evolved from a neutrophil activating protein.
Clark-Lewis
I
I
Biomedical Research Center, University of British Columbia, Vancouver, Canada.
Dewald
B
B
Geiser
T
T
Moser
B
B
Baggiolini
M
M
D000595:Amino Acid Sequence; D002118:Calcium / Q000097:blood; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003571:Cytochalasin B / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D016209:Interleukin-8 / Q000378:metabolism; D007700:Kinetics; D019272:Leukocyte Elastase; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D010196:Pancreatic Elastase / Q000378:metabolism; D010978:Platelet Factor 4 / Q000138:chemical synthesis / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000187:drug effects / Q000502:physiology*; D023062:Receptors, Interleukin-8A; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
D016209:Interleukin-8; D011971:Receptors, Immunologic; D023062:Receptors, Interleukin-8A; D010978:Platelet Factor 4; D003571:Cytochalasin B; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase; D002118:Calcium