title: Inhibition of airway inflammation by amino-terminally modified RANTES/CC chemokine ligand 5 analogues is not mediated through CCR3.
abstract: Chemokines play a key role in the recruitment of activated CD4(+) T cells and eosinophils into the lungs in animal models of airway inflammation. Inhibition of inflammation by N-terminally modified chemokines is well-documented in several models but is often reported with limited dose regimens. We have evaluated the effects of doses ranging from 10 ng to 100 micro g of two CC chemokine receptor antagonists, Met-RANTES/CC chemokine ligand 5 (CCL5) and aminooxypentane-RANTES/CCL5, in preventing inflammation in the OVA-sensitized murine model of human asthma. In the human system, aminooxypentane-RANTES/CCL5 is a full agonist of CCR5, but in the murine system neither variant is able to induce cellular recruitment. Both antagonists showed an inverse bell-shaped inhibition of cellular infiltration into the airways and mucus production in the lungs following allergen provocation. The loss of inhibition at higher doses did not appear to be due to partial agonist activity because neither variant showed activity in recruiting cells into the peritoneal cavity at these doses. Surprisingly, neither was able to bind to the major CCR expressed on eosinophils, CCR3. However, significant inhibition of eosinophil recruitment was observed. Both analogues retained high affinity binding for murine CCR1 and murine CCR5. Their ability to antagonize CCR1 and CCR5 but not CCR3 was confirmed by their ability to prevent RANTES/CCL5 and macrophage inflammatory protein-1beta/CCL4 recruitment in vitro and in vivo, while they had no effect on that induced by eotaxin/CCL11. These results suggest that CCR1 and/or CCR5 may be potential targets for asthma therapy.
authors: Serono Pharmaceutical Research Institute, Plan les Ouates, Geneva, Switzerland.
authors: Yolande
authors: Y
authors: Chvatchko
authors: Amanda E I
authors: AE
authors: Proudfoot
authors: Raphaële
authors: R
authors: Buser
authors: Pierre
authors: P
authors: Juillard
authors: Sami
authors: S
authors: Alouani
authors: Marie
authors: M
authors: Kosco-Vilbois
authors: Anthony J
authors: AJ
authors: Coyle
authors: Robert J
authors: RJ
authors: Nibbs
authors: Gerry
authors: G
authors: Graham
authors: Robin E
authors: RE
authors: Offord
authors: Timothy N C
authors: TN
authors: Wells
mesh_terms: D000485:Allergens / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D001667:Binding, Competitive / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000473:pathology; D016466:CHO Cells; D002460:Cell Line; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000276:immunology; D018946:Chemokine CCL5 / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000235:genetics / Q000494:pharmacology; D006224:Cricetinae; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D010529:Peritoneal Cavity / Q000166:cytology; D017434:Protein Structure, Tertiary / Q000235:genetics; D054397:Receptors, CCR3; D019713:Receptors, CCR5 / Q000008:administration & dosage* / Q000235:genetics / Q000502:physiology; D019707:Receptors, Chemokine / Q000502:physiology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000485:Allergens; C515350:CCR3 protein, human; C515351:Ccr3 protein, mouse; D018946:Chemokine CCL5; C108335:RANTES, Met-; D054397:Receptors, CCR3; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; C111989:aminooxypentane-RANTES; D010047:Ovalbumin