CC chemokine ligand 11 (CCL11/eotaxin) and other CC chemokine receptor 3 (CCR3) ligands (CCL24/eotaxin-2, CCL26/ eotaxin-3, CCL13/monocyte chemotactic protein-4, etc.) play important roles in the chemotaxis and activation of eosinophils and other CCR3-expressing cells (basophils, mast cells, and CD4 ϩ T helper 2 cells) in allergic inflammation incidents, including asthma and rhinitis. A newly synthesized compound, (1 mg/kg) inhibited CCL11-induced shape change of whole blood eosinophils in cynomolgus monkeys. Intravenous injection of YM-355179 (1 mg/kg) also inhibited eosinophil infiltration into airways of cynomolgus monkeys after segmental bronchoprovocation with CCL11. These results indicate that YM-355179 is a novel, selective, and orally available CCR3 antagonist with therapeutic potential for treating eosinophil-related allergic inflammatory diseases.Eosinophils play a crucial role in allergic diseases such as bronchial asthma and allergic rhinitis (Durham and Kay, 1985;Terada et al., 1994). CCR3, a seven-transmembranespanning G protein-coupled receptor, is a major chemokine receptor expressed on allergic inflammatory cells including not only eosinophils but also basophils, mast cells, and T helper 2-type CD4 ϩ cells (Combadiere et al., 1995;Post et al., 1995;Sabroe et al., 1998). This receptor has been identified in humans, monkeys, mice, rats, and guinea pigs (GarciaZepeda et al., 1996;Forssmann et al., 1997;Sallusto et al., 1997;Zhang et al., 2002). Human CCR3 binds multiple chemokine ligands such as CCL11/eotaxin, CCL24/eotaxin-2, CCL26/eotaxin-3, and CCL13/MCP-4 with high affinity, whereas CCR3 binds CCL5/regulated on activation normal T cell expressed and secreted and CCL7/MCP-3 with lower affinity (Forssmann et al., 1997;Stellato et al., 1997;Doucet et al., 1998). CCR3 ligands are produced by multiple cell types, including lung and mucosal fibroblast cells, bronchial epithelial cells, vascular endothelial cells, smooth muscle cells, macrophages, mast cells, and eosinophils (Lamkhioued et al., 1997;Lilly et al., 1997;Shinkai et al., 1999;Hirst et al., 2002;Menzies-Gow et al., 2004). The binding of CCR3 ligands to CCR3 on the surface of eosinophils causes a transient increase in intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) that activates several signal pathways, including actin polymerization (Elsner et al., 1996). With activation of the intracellular motile apparatus, eosinophils undergo shape change
Since the expression profiles of cytokines and chemokines correspond well with those in human IBD, MDR1a-/- mouse is a useful model for the analysis of IBD pathophysiology.
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