Interleukin 8 dimerization as a mechanism for regulation of neutrophil adherence-dependent oxidant production.
Interleukin 8 (IL-8), a member of the CXC subfamily of chemoattractant cytokines, induces a range of functional responses in human neutrophils via its interactions with two high-affinity cell-surface receptors, CXCR1 and CXCR2. Like other CXC chemokines, IL-8 forms homodimers at physiologic concentrations. Monomers and dimers bind to CXC receptors with high affinity and induce various functions. Binding to glycosaminoglycans decreases the dimerization constant, enhancing surface-bound dimer formation. However, a specific role for IL-8 dimerization has not been identified. We explored the hypothesis that certain neutrophil responses to IL-8 were induced primarily by the IL-8 dimers. To this end, two dimerization-deficient IL-8 mutant proteins, M3 and M4, were used in various functional assays. In contrast to native IL-8, these proteins existed primarily as monomers at micromolar concentrations. The mutants retained high-affinity binding to both CXC receptors and potently induced neutrophil calcium flux, chemotaxis, and elastase release. In contrast to native IL-8, neither mutant inhibited tumor necrosis factor alpha-induced oxidant production. Additionally, M4 was less effective than native IL-8 at desensitizing neutrophil migration. These data suggest that although IL-8 dimers or monomers are sufficient for several neutrophil functions, dimers may participate in suppression of specific surface-dependent neutrophil responses.
Williams
Mark A
MA
Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0558, USA.
Cave
Cindy M
CM
Quaid
Gina
G
Robinson
Chad
C
Daly
Thomas J
TJ
Witt
Dan
D
Lentsch
Alex B
AB
Solomkin
Joseph S
JS
D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion; D018925:Chemokines / Q000378:metabolism; D002633:Chemotaxis; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D005609:Free Radicals; D006025:Glycosaminoglycans / Q000737:chemistry; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D016209:Interleukin-8 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009504:Neutrophils / Q000166:cytology* / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D010196:Pancreatic Elastase / Q000378:metabolism; D011869:Radioligand Assay; D023062:Receptors, Interleukin-8A / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D016897:Respiratory Burst; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018925:Chemokines; D005609:Free Radicals; D006025:Glycosaminoglycans; D016209:Interleukin-8; D016877:Oxidants; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D014409:Tumor Necrosis Factor-alpha; D006861:Hydrogen Peroxide; D010196:Pancreatic Elastase; D010100:Oxygen; D002118:Calcium