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An engineered CX3CR1 antagonist endowed with anti-inflammatory activity

Dorgham, Karim
Ghadiri, Ata
Hermand, Patricia
Rodero, Mathieu
Poupel, Lucie
Iga, Mutsumori
Gorochov, Guy
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Published in Journal of leukocyte biology. 2009, vol. 86, no. 4, p. 903-911
Abstract Chemokines are mainly involved in the recruitment of leukocytes into tissues, a key feature of inflammation. Through its unique receptor CX3CR1, the chemokine CX3CL1 participates in diverse inflammatory processes including arterial atherosclerosis and cerebral or renal inflammation. Using a phage display strategy, we engineered a hCX3CL1 analog (named F1) with a modified N terminus. F1 bound specifically to cells expressing hCX3CR1 and had a K(d) value close to that of native CX3CL1. F1 was not a signaling molecule and did not induce chemotaxis, calcium flux, or CX3CR1 internalization. However, it potently inhibited the CX3CL1-induced calcium flux and chemotaxis in CX3CR1-expressing primary cells of human and murine origin with an IC(50) of 5-50 nM. It also efficiently inhibited the cell adhesion mediated by the CX3CL1-CX3CR1 axis. Finally, in a noninfectious murine model of peritonitis, F1 strongly inhibited macrophage accumulation. These data reveal a prototype molecule that is the first bona fide antagonist of hCX3CR1. This molecule could be used as a lead compound for the development of a novel class of anti-inflammatory substances that act by inhibiting CX3CR1.
Keywords AnimalsAnti-Inflammatory Agents, Non-Steroidal/*pharmacologyCHO CellsCalcium/metabolismCell Adhesion/drug effectsChemokine CX3CL1/metabolismChemotaxis/*drug effectsCricetinaeCricetulusDisease Models, AnimalDose-Response Relationship, DrugHumansInflammation/drug therapy/metabolismMacrophages, Peritoneal/*metabolismMicePeptides/*pharmacologyPeritonitis/drug therapy/metabolismReceptors, Chemokine/*antagonists & inhibitors/metabolism
PMID: 19571253
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Other version: http://www.jleukbio.org/content/86/4/903.full.pdf
Research group HIV (835)
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DORGHAM, Karim et al. An engineered CX3CR1 antagonist endowed with anti-inflammatory activity. In: Journal of leukocyte biology, 2009, vol. 86, n° 4, p. 903-911. doi: 10.1189/jlb.0308158 https://archive-ouverte.unige.ch/unige:19779

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Deposited on : 2012-04-23

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