Inhibition by troglitazone of the antigen-induced production of leukotrienes in immunoglobulin E-sensitized RBL-2H3 cells.
1. The effect of troglitazone, an anti-diabetic drug with insulin-sensitizing action, on antigen-induced production of leukotriene (LT) B(4), C(4) and E(4) and prostaglandin D(2) (PGD(2)) was examined in dinitrophenol (DNP)-specific immunoglobulin E (IgE)-sensitized RBL-2H3 mast cells following stimulation by the antigen, DNP-conjugated human serum albumin. Levels of LTB(4), C(4) and E(4) and PGD(2) in the conditioned medium were enzyme-immunoassayed. 2. Troglitazone inhibited the antigen-induced production of LTB(4), C(4) and E(4) and the potency of the inhibition was comparable to that of zileuton, a specific inhibitor of 5-lipoxygenase (5-LOX) and a clinically used anti-asthmatic drug. Neither troglitazone nor zileuton affected antigen-induced production of PGD(2), arachidonic acid release from membrane phospholipids and degranulation. 3. Troglitazone inhibited LTB(4) production by the supernatant fraction of RBL-2H3 cell lysate with similar potency to zileuton, suggesting that troglitazone inhibits LT production by direct inhibition of 5-LOX activity. 4. Furthermore, it was shown that troglitazone as well as zileuton inhibited LTB(4) production in A23187-stimulated rat peritoneal neutrophils. 5. These findings suggest that troglitazone inhibits antigen-induced LT production in the IgE-sensitized RBL-2H3 cells and A23187-stimulated rat peritoneal neutrophils by direct inhibition of 5-LOX activity.
Yamashita
M
M
Department of Pathophysiological Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
Kushihara
M
M
Hirasawa
N
N
Takasaki
W
W
Takahagi
H
H
Takayanagi
M
M
Ohuchi
K
K
D000818:Animals; D000941:Antigens / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D015550:Cell Degranulation / Q000187:drug effects; D002460:Cell Line; D002839:Chromans / Q000494:pharmacology*; D017077:Culture Media, Conditioned; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007073:Immunoglobulin E / Q000276:immunology*; D007975:Leukotriene B4 / Q000096:biosynthesis; D017997:Leukotriene C4 / Q000096:biosynthesis; D017999:Leukotriene E4 / Q000096:biosynthesis; D015289:Leukotrienes / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D015230:Prostaglandin D2 / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone
D000941:Antigens; D002839:Chromans; D017077:Culture Media, Conditioned; D007004:Hypoglycemic Agents; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D013844:Thiazoles; D045162:Thiazolidinediones; D007975:Leukotriene B4; D016718:Arachidonic Acid; D017997:Leukotriene C4; D007073:Immunoglobulin E; D000001:Calcimycin; D017999:Leukotriene E4; D000077288:Troglitazone; D015230:Prostaglandin D2; C063449:zileuton; D006918:Hydroxyurea