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

Eur J Pharmacol. 2007 Apr 10;560(2-3):225-33. doi: 10.1016/j.ejphar.2007.01.012. Epub 2007 Jan 19.

Abstract

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.

MeSH terms

  • Anilides / pharmacology*
  • Animals
  • Antigens / immunology
  • Asthma / drug therapy*
  • Calcium / metabolism*
  • Calcium Channels / drug effects*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Eosinophilia / prevention & control*
  • Female
  • Guinea Pigs
  • Humans
  • Interleukin-4 / antagonists & inhibitors*
  • Interleukin-4 / biosynthesis
  • Interleukin-5 / antagonists & inhibitors*
  • Interleukin-5 / biosynthesis
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Rats
  • Rats, Inbred BN
  • Thiadiazoles / pharmacology*

Substances

  • 4-methyl-4'-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)-1,2,3-thiadiazole-5-carboxanilide
  • Anilides
  • Antigens
  • Calcium Channels
  • Interleukin-5
  • Thiadiazoles
  • Interleukin-4
  • Calcium