YM-58483, a selective CRAC channel inhibitor, prevents antigen-induced airway eosinophilia and late phase asthmatic responses via Th2 cytokine inhibition in animal models

• Published in: European journal of pharmacology 2007-04, Vol.560 (2), p.225-233
• Main Authors: Yoshino, Taiji, Ishikawa, Jun, Ohga, Keiko, Morokata, Tatsuaki, Takezawa, Ryuichi, Morio, Hiroki, Okada, Youhei, Honda, Kazuo, Yamada, Toshimitsu
• Format: Article
• Language: English
• Subjects: Anilides - pharmacology; Animals; Antigens - immunology; Asthma; Asthma - drug therapy; Biological and medical sciences; Calcium - metabolism; Calcium Channels - drug effects; Chronic obstructive pulmonary disease, asthma; CRAC channel; Disease Models, Animal; Dose-Response Relationship, Drug; Eosinophilia - prevention & control; Eosinophilic inflammation; Female; Guinea Pigs; Humans; Interleukin-4 - antagonists & inhibitors; Interleukin-4 - biosynthesis; Interleukin-5 - antagonists & inhibitors; Interleukin-5 - biosynthesis; Male; Medical sciences; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Pharmacology. Drug treatments; Pneumology; Rats; Rats, Inbred BN; T helper type 2 cytokine; Thiadiazoles - pharmacology; YM-58483
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2007.01.012

T cells play a regulatory role in the pathogenesis of various immune and allergic diseases, including human asthma. Recently, it was reported that a pyrazole derivative, YM-58483 (BTP2), potently inhibits Ca 2+ release-activated Ca 2+ (CRAC) channels and interleukin (IL)-2 production in T cells. We investigated the effects of YM-58483 on T helper type 2 (Th2) cytokine production in vitro and antigen-induced airway asthmatic responses in vivo. YM-58483 inhibited IL-4 and IL-5 production in a conalbumine-stimulated murine Th2 T cell clone (D10.G4.1), and IL-5 production in phytohemagglutinin-stimulated human whole blood cells with IC 50 values comparable to those reported for its CRAC channel inhibition (around 100 nM). YM-58483 inhibited antigen-induced eosinophil infiltration into airways, and decreased IL-4 and cysteinyl-leukotrienes content in inflammatory airways induced in actively sensitized Brown Norway rats. Furthermore, orally administered YM-58483 prevented antigen-induced late phase asthmatic broncoconstriction and eosinophil infiltration in actively sensitized guinea pigs. These data suggest that the inhibition of Ca 2+ influx through CRAC channel leads to the prevention of antigen-induced airway inflammation, probably via the inhibition of Th2 cytokine production and inflammatory mediators release. YM-58483 may therefore be useful for treating airway inflammation in bronchial asthma.