title: TA-270 [4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone], an anti-asthmatic agent, inhibits leukotriene production induced by IgE receptor stimulation in RBL-2H3 cells.
abstract: A novel quinolinone derivative, TA-270 [4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone], has been shown to inhibit antigen-induced asthmatic responses including the early-phase bronchoconstriction in actively sensitized guinea pigs. Here we characterized the action mechanisms of TA-270 in cellular level in vitro. In RBL-2H3 mast cells sensitized with dinitrophenol (DNP)-specific IgE, the antigen exhibited several mast cell functions, including hexosaminidase release as a marker of degranulation, production of tumor necrosis factor-alpha, and production of immunologically detective leukotrienes. These antigen-induced actions were associated with the activation of several early signaling events, including inositol phosphate production reflecting phospholipase C activation and extracellular signal-regulated kinase activation. When the cells were treated with TA-270, the antigen-induced leukotriene production was almost completely suppressed, but other antigen-induced actions listed above were hardly affected. This drug also failed to affect the antigen-induced phospholipase A2 activation as evaluated by the total release of arachidonic acid and its metabolites from the cells prelabeled with radioactive arachidonic acid. However, TA-270 clearly changed the arachidonic acid metabolic pathway. It suppressed the accumulation of 5-lipoxygenase products, including leukotrienes, but hardly affected the accumulation of cyclooxygenase products. The inhibitory action of TA-270 on leukotriene production was also observed in human neutrophils and eosinophils. We conclude that TA-270 inhibits 5-lipoxygenase activity and, thereby, suppresses the antigen-induced leukotriene production.
authors.affiliation: Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan. fokajima@showa.gunma-u.ac.jp
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Ishiwara
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Aoki
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Takagaki
authors.forename: Michio
authors.initials: M
authors.lastname: Ui
authors.forename: Fumikazu
authors.initials: F
authors.lastname: Okajima
mesh_terms: D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D002478:Cells, Cultured; D002934:Cinnamates / Q000494:pharmacology*; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D015289:Leukotrienes / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors; D008407:Mast Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology*; D017455:Receptors, IgE / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
chemical_list: D018927:Anti-Asthmatic Agents; D002934:Cinnamates; D007476:Ionophores; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D015363:Quinolones; D017455:Receptors, IgE; C420451:TA 270; D014409:Tumor Necrosis Factor-alpha; D000001:Calcimycin; D001094:Arachidonate 5-Lipoxygenase; D001619:beta-N-Acetylhexosaminidases