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CXC-chemokine receptors 1 and 2 and their ligands (CXCL1, 2, 3, 5, 6, 7, and 8) induce the selective recruitment of neutrophils during inflammation. Such receptors have not been characterized yet in guinea pig, an animal inflammation model of interest. We report the identification, cloning, and characterization of a CXCL8 receptor in guinea pig. Human CXCL8 produced in vivo neutrophilia, chemotaxis and intracellular calcium release of guinea pig neutrophils. The expression of this receptor at their neutrophil surface was investigated. The cDNA encoding a functional CXCL8 receptor was cloned from guinea pig neutrophils and sequenced. It was synthesized using RT-PCR, with oligonucleotide primers derived from well conserved regions of published CXCL8 receptors. This sequence presented an open reading frame coding for 352 amino acids and shares, at the amino acid level, 70 and 69% identity with human and rabbit CXCR2, respectively. The receptor was mainly expressed in neutrophils but it was also present in kidney, lung, spleen and, to a less extent, in heart. Cloned receptor transfected cells showed that this receptor displayed high affinity for human CXCL8, slightly lower than the affinity observed with guinea pig neutrophils. CXC chemokines from both rabbit and human were shown to induce inositol phosphate accumulation in these transfected cells. Receptor binding and activation characteristics together with sequence homology suggested that we identified a guinea pig equivalent of the human CXCR2 receptor.