Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
9002169 | Biochemical Pharmacology | 2005 | 10 Pages |
Abstract
Repertaxin is a new non-competitive allosteric blocker of interleukin-8 (CXCL8/IL-8) receptors (CXCR1/R2), which by locking CXCR1/R2 in an inactive conformation prevents receptor signaling and human polymorphonuclear leukocyte (PMN) chemotaxis. Given the unique mode of action of repertaxin it was important to examine the ability of repertaxin to inhibit a wide range of biological activities induced by CXCL8 in human leukocytes. Our results show that repertaxin potently and selectively blocked PMN adhesion to fibrinogen and CD11b up-regulation induced by CXCL8. Reduction of CXCL8-mediated PMN adhesion by repertaxin was paralleled by inhibition of PMN activation including secondary and tertiary granule release and pro-inflammatory cytokine production, whereas PMN phagocytosis of Escherichia coli bacteria was unaffected. Repertaxin also selectively blocked CXCL8-induced T lymphocyte and natural killer (NK) cell migration. These data suggest that repertaxin is a potent and specific inhibitor of a wide range of CXCL8-mediated activities related to leukocyte recruitment and functional activation in inflammatory sites.
Keywords
IL-1βCXCR1N-formyl-methionyl-leucyl-phenylalaninefMLPCXCL12/SDF-1C5aPMNCXCR2Granulocyte chemotactic protein-2GPCRCXCL8/IL-8MMP-9GAPDHPBSFBSLPSnatural killerEDTAethylenediaminetetracetic acidBacterial endotoxinInterleukin-8Interleukin-1βfetal bovine serumstromal cell-derived factor-1PhagocytosisPhosphate buffered salineDegranulationHuman polymorphonuclear leukocytespolymorphonuclear leukocytesMatrix metalloproteinase 9Adhesionglyceraldehyde-3-phosphate dehydrogenaseG protein-coupled receptor
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Authors
Federica Casilli, Andrea Bianchini, Isabelle Gloaguen, Leda Biordi, Edoardo Alesse, Claudio Festuccia, Barbara Cavalieri, Raffaele Strippoli, Maria Neve Cervellera, Rosa Di Bitondo, Elisabetta Ferretti, Fabrizio Mainiero, Cinzia Bizzarri,