YM-58483, a selective CRAC channel inhibitor, prevents antigen-induced airway eosinophilia and late phase asthmatic responses via Th2 cytokine inhibition in animal models.
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 bronchoconstriction 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.
Yoshino
Taiji
T
Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. taiji.yoshino@jp.astellas.com
Ishikawa
Jun
J
Ohga
Keiko
K
Morokata
Tatsuaki
T
Takezawa
Ryuichi
R
Morio
Hiroki
H
Okada
Youhei
Y
Honda
Kazuo
K
Yamada
Toshimitsu
T
D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D000941:Antigens / Q000276:immunology; D001249:Asthma / Q000188:drug therapy*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004802:Eosinophilia / Q000517:prevention & control*; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D015847:Interleukin-4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D015848:Interleukin-5 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D051381:Rats; D011914:Rats, Inbred BN; D013830:Thiadiazoles / Q000494:pharmacology*
C476308:4-methyl-4'-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)-1,2,3-thiadiazole-5-carboxanilide; D000813:Anilides; D000941:Antigens; D015220:Calcium Channels; D015848:Interleukin-5; D013830:Thiadiazoles; D015847:Interleukin-4; D002118:Calcium