Biomolecules & Therapeutics

  • 제28권5호
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  • Pages.456-464
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  • 2020
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  • 1976-9148(pISSN)
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  • 2005-4483(eISSN)
한국응용약물학회 (The Korean Society of Applied Pharmacology)
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Dasatinib Inhibits Lyn and Fyn Src-Family Kinases in Mast Cells to Suppress Type I Hypersensitivity in Mice

  • Lee, Dajeong (Department of Immunology, College of Medicine, Konkuk University) ;
  • Park, Young Hwan (Department of Immunology, College of Medicine, Konkuk University) ;
  • Lee, Ji Eon (Department of Immunology, College of Medicine, Konkuk University) ;
  • Kim, Hyuk Soon (Department of Immunology, College of Medicine, Konkuk University) ;
  • Min, Keun Young (Department of Immunology, College of Medicine, Konkuk University) ;
  • Jo, Min Geun (Department of Immunology, College of Medicine, Konkuk University) ;
  • Kim, Hyung Sik (Division of Toxicology, College of Pharmacy, Sungkyunkwan University) ;
  • Choi, Wahn Soo (Department of Immunology, College of Medicine, Konkuk University) ;
  • Kim, Young Mi (College of Pharmacy, Duksung Women's University)
  • 투고 : 2020.01.30
  • 심사 : 2020.03.13
  • 발행 : 2020.09.01
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초록

Mast cells (MCs) are systemically distributed and secrete several allergic mediators such as histamine and leukotrienes to cause type I hypersensitivity. Dasatinib is a type of anti-cancer agent and it has also been reported to inhibit human basophils. However, dasatinib has not been reported for its inhibitory effects on MCs or type I hypersensitivity in mice. In this study, we examined the inhibitory effect of dasatinib on MCs and MC-mediated allergic response in vitro and in vivo. In vitro, dasatinib inhibited the degranulation of MCs by antigen stimulation in a dose-dependent manner (IC50, ~34 nM for RBL-2H3 cells; ~52 nM for BMMCs) without any cytotoxicity. It also suppressed the secretion of inflammatory cytokines IL-4 and TNF-α by antigen stimulation. Furthermore, dasatinib inhibited MC-mediated passive cutaneous anaphylaxis (PCA) in mice (ED50, ~29 mg/kg). Notably, dasatinib significantly suppressed the degranulation of MCs in the ear tissue. As the mechanism of its effect, dasatinib inhibited the activation of Syk and Syk-mediated downstream signaling proteins, LAT, PLCγ1, and three typical MAP kinases (Erk1/2, JNK, and p38), which are essential for the activation of MCs. Interestingly, in vitro tyrosine kinase assay, dasatinib directly inhibited the activities of Lyn and Fyn, the upstream tyrosine kinases of Syk in MCs. Taken together, dasatinib suppresses MCs and PCA in vitro and in vivo through the inhibition of Lyn and Fyn Src-family kinases. Therefore, we suggest the possibility of repositioning the anti-cancer drug dasatinib as a treatment for various MC-mediated type I hypersensitive diseases.

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참고문헌

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