4-Chlorotetrazolo[1,5-a]quinoxaline inhibits activation of Syk kinase to suppress mast cells in vitro and mast cell-mediated passive cutaneous anaphylaxis in mice |
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Authors: | Park Kui Lea Ko Na Young Lee Jun Ho Kim Do Kyun Kim Hyuk Soon Kim A-Ram Her Erk Kim Bokyung Kim Hyung Sik Moon Eun-Yi Kim Young Mi Kim Hang-Rae Choi Wahn Soo |
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Affiliation: | a Center for Drug Development Assistance, National Institute of Food Drug Safety Evaluation (NIFDS), KFDA, Cheongwon-gun, Republic of Koreab Department of Immunology and physiology, College of Medicine, Konkuk University, Chungju, Republic of Koreac College of Pharmacy, Pusan National University, Busan, Republic of Koread Department of Bioscience and Biotechnology, College of Biological Science, Sejong University, Seoul, Republic of Koreae College of Pharmacy, Duksung Women's University, Seoul, Republic of Koreaf Department of Anatomy, Seoul National University College of Medicine, Seoul, Republic of Korea |
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Abstract: | 4-Chlorotetrazolo[1,5-a]quinoxaline is a quinoxaline derivative. We aimed to study the effects of 4-chlorotetrazolo[1,5-a]quinoxaline on activation of mast cells in vitro and in mice. 4-Chlorotetrazolo[1,5-a]quinoxaline reversibly inhibited degranulation of mast cells in a dose-dependent manner, and also suppressed the expression and secretion of TNF-α and IL-4 in mast cells. Mechanistically, 4-chlorotetrazolo[1,5-a]quinoxaline inhibited activating phosphorylation of Syk and LAT, which are crucial for early FcεRI-mediated signaling events, as well as Akt and MAP kinases, which play essential roles in the production of various pro-inflammatory cytokines in mast cells. Notably, although 4-chlorotetrazolo[1,5-a]quinoxaline inhibited the activation of Fyn and Syk, minimal inhibition was observed in mast cells in the case of Lyn. Furthermore, consistent with its in vitro activity, 4-chlorotetrazolo[1,5-a]quinoxaline significantly suppressed mast cell-mediated passive cutaneous anaphylaxis in mice. In summary, the results from this study demonstrate that 4-chlorotetrazolo[1,5-a]quinoxaline shows an inhibitory effect on mast cells in vitro and in vivo, and that this is mediated by inhibiting the activation of Syk in mast cells. Therefore, 4-chlorotetrazolo[1,5-a]quinoxaline could be useful in the treatment of mast cell-mediated allergic diseases. |
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Keywords: | 4-Chlorotetrazolo[1,5-a]quinoxaline Mast cells Syk Allergy Passive cutaneous anaphylaxis |
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