title: Diverging mechanisms of activation of chemokine receptors revealed by novel chemokine agonists.
abstract: CXCL8/interleukin-8 is a pro-inflammatory chemokine that triggers pleiotropic responses, including inflammation, angiogenesis, wound healing and tumorigenesis. We engineered the first selective CXCR1 agonists on the basis of residue substitutions in the conserved ELR triad and CXC motif of CXCL8. Our data reveal that the molecular mechanisms of activation of CXCR1 and CXCR2 are distinct: the N-loop of CXCL8 is the major determinant for CXCR1 activation, whereas the N-terminus of CXCL8 (ELR and CXC) is essential for CXCR2 activation. We also found that activation of CXCR1 cross-desensitized CXCR2 responses in human neutrophils co-expressing both receptors, indicating that these novel CXCR1 agonists represent a new class of anti-inflammatory agents. Further, these selective CXCR1 agonists will aid at elucidating the functional significance of CXCR1 in vivo under pathophysiological conditions.
authors.affiliation: Departments of Neuroscience and Cell Biology, The University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Jose
authors.initials: J
authors.lastname: Sarmiento
authors.forename: Christie
authors.initials: C
authors.lastname: Shumate
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Suetomi
authors.forename: Aishwarya
authors.initials: A
authors.lastname: Ravindran
authors.forename: León
authors.initials: L
authors.lastname: Villegas
authors.forename: Krishna
authors.initials: K
authors.lastname: Rajarathnam
authors.forename: Javier
authors.initials: J
authors.lastname: Navarro
mesh_terms: D002118:Calcium / Q000378:metabolism; D018925:Chemokines / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D004705:Endocytosis; D018922:HL-60 Cells; D006801:Humans; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding; D015202:Protein Engineering; D019707:Receptors, Chemokine / Q000737:chemistry / Q000378:metabolism*; D023062:Receptors, Interleukin-8A / Q000378:metabolism
chemical_list: D018925:Chemokines; D050505:Mutant Proteins; D019707:Receptors, Chemokine; D023062:Receptors, Interleukin-8A; D002118:Calcium