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INFLAMMATION AND IMMUNOPHARMACOLOGY

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

Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan (M.I., F.O.); Central Research Laboratories, Dainippon Ink and Chemicals, Inc., Sakura-shi, Chiba, Japan (M.I., Y.A., H.T.); and Tokyo Metropolitan Institute of Medical Science, Honkomagome, Tokyo, Japan (M.U.)

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-, 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.

Address correspondence to: Fumikazu Okajima, Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan. E-mail: fokajima{at}showa.gunma-u.ac.jp