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INFLAMMATION AND IMMUNOPHARMACOLOGY

Cloning and Pharmacological Characterization of CXCR1 and CXCR2 from Macaca fascicularis

Department of Immunology, Schering-Plough Research Institute, Kenilworth, New Jersey

Two genes with high sequence homology to human CXCR1 (hCXCR1) and CXCR2 (hCXCR2) were cloned from blood of cynomolgus monkey (Macaca fascicularis). Comparison of the expression pattern of these receptors in different species demonstrated that, like in humans, cynomolgus CXCR1 (cCXCR1) and CXCR2 (cCXCR2) are highly expressed in blood. Membranes from transfected BaF3 cells expressing cCXCR1 bind interleukin (IL)-8 with an affinity similar to hCXCR1 (K_d values, 170 ± 87 and 103 ± 37 pM, respectively) and show low binding affinity to Gro-. Cynomolgus CXCR2 also binds hIL-8 but with somewhat higher affinity than the hCXCR2 (46 ± 28 and 220 ± 14 pM, respectively). Surprisingly, cCXCR2 has a reduced binding affinity to hGro- (3.7 ± 2.2 nM), a specific ligand of hCXCR2 (540 ± 140 pM). Furthermore, the CXCR2-specific antagonist SB225002 [N-(2-hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea] is 10-fold more potent in inhibiting IL-8 binding to hCXCR2 than to cCXCR2, suggesting that some of the observed differences in the amino acid sequences of the human and monkey receptor affect ligand binding sites or the conformation of the receptor. Both cynomolgus receptors were functionally active in inducing guanosine 5'-O-(3-thio)triphosphate exchange on membranes in response to IL-8 and Gro- and in mediating chemotactic activity of recombinant BA/F3 cells in response to IL-8 and Gro-. These results identify the products of the novel cynomolgus genes as functional homologs of hCXCR1 and hCXCR2.

Address correspondence to: Dr. Maria Wiekowski, Department of Immunology, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033. E-mail: maria.wiekowski{at}spcorp.com

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