Chemokine receptor inhibitor, Antileukinate, suppressed ovalbumin-induced eosinophilic inflammation in the airway.
Accumulating evidence suggests that eosinophils play an important role in the pathogenesis of allergic diseases. An eosinophil-active chemokine, eotaxin, and its receptor, C-C chemokine receptor 3, are particularly attractive as novel targets of immunological intervention for the disease. In this study, we examine the effects of a hexa-peptide (Ac-RRWWCR-NH(2)), Antileukinate, which we have previously defined as a potent inhibitor of CXC chemokine receptor 1 and 2, on eotaxin in vitro and in vivo. Antileukinate inhibited the binding of 125I-labeled human eotaxin to human eosinophils with an IC(50) of approximately 10 microM and eosinophil chemotaxis to human eotaxin was significantly inhibited by 10 microM of Antileukinate. We examined the effects of Antileukinate on eosinophil accumulation induced by intraperitoneal administration of murine eotaxin, and confirmed that Antileukinate is also active in the murine system. When Antileukinate was tested in ovalbumin-induced airway inflammation model in vivo, Antileukinate significantly inhibited eosinophil accumulation and allergen-induced increase in total protein in bronchoalveolar lavage fluids. Furthermore, Antileukinate suppressed fibrous thickening of submucosal tissue induced by chronic antigen challenge. These results suggest that eotaxin is involved in the pathogenesis of eosinophilic airway inflammation, and that Antileukinate may be a promising tool to control allergic diseases.
Fukuno
Yuji
Y
Department of Medicine, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan.
Hayashi
Shinichiro
S
Kohsa
Kazuhiro
K
Fujisawa
Nobumitsu
N
Tominaga
Masaki
M
Miller
Edmund J
EJ
Nagasawa
Kohei
K
D000818:Animals; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004802:Eosinophilia / Q000139:chemically induced; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology*; D010047:Ovalbumin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012119:Respiration / Q000187:drug effects
C515456:CCL11 protein, human; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D009842:Oligopeptides; D019707:Receptors, Chemokine; C118980:antileukinate; D010047:Ovalbumin