Amino terminus of the interleukin-8 receptor is a major determinant of receptor subtype specificity.
Interleukin-8 (IL-8) is a key mediator in the migration of neutrophils from the circulation to the site of inflammation in the tissue. IL-8 is secreted by many cell types in response to proinflammatory stimuli such as interleukin 1, tumor necrosis factor, and lipopolysaccharide and is a potent chemoattractant and activator of neutrophils. Neutrophil activating peptide-2 (NAP-2) and melanoma growth-stimulatory activity (MGSA/GRO) are structurally and functionally related to IL-8 and, like IL-8, bind to specific G protein-coupled receptors on neutrophils. In the present study two closely related cloned IL-8 receptor subtypes are characterized by expression of the cDNA clones in monkey kidney cells (COS-7) or chinese hamster ovary cells and analysis of their ligand binding profiles. Both receptor subtypes bind 125I-labeled IL-8 with similar high affinity, however, the F3R receptor binds IL-8 exclusively, while the 4Ab receptor binds both IL-8 and MGSA/GRO with high affinity and NAP-2 with lesser affinity. Furthermore, we demonstrate with the use of intersubtype chimeric receptors that the specificity of ligand binding to both IL-8 receptor subtypes is dictated by the heterogeneous NH2-terminal domain. The F3R receptor is representative of a restricted IL-8 receptor subtype, and 4Ab represents a nonrestricted receptor subtype. It is proposed that these subtypes be named IL-8 receptors alpha and beta, respectively.
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D003001:Cloning, Molecular; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D015723:Gene Library; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D007700:Kinetics; D007962:Leukocytes / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology; D008961:Models, Structural; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000276:immunology; D009928:Organ Specificity; D010957:Plasmids; D017433:Protein Structure, Secondary; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D011971:Receptors, Immunologic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D023062:Receptors, Interleukin-8A; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D014162:Transfection
D016209:Interleukin-8; D011971:Receptors, Immunologic; D023062:Receptors, Interleukin-8A; D011993:Recombinant Fusion Proteins; D012313:RNA; D004247:DNA