title: An indoxyl compound 5-bromo-4-chloro-3-indolyl 1,3-diacetate, CAC-0982, suppresses activation of Fyn kinase in mast cells and IgE-mediated allergic responses in mice.
abstract: Mast cells, constituents of virtually all organs and tissues, are critical cells in IgE-mediated allergic responses. The aim of this study was to investigate the effect and mechanism of an indoxyl chromogenic compound, 5-bromo-4-chloro-3-indolyl 1,3-diacetate, CAC-0982, on IgE-mediated mast cell activation and allergic responses in mice. CAC-0982 reversibly suppressed antigen-stimulated degranulation in murine mast cells (IC50, ~3.8μM) and human mast cells (IC50, ~3.0μM). CAC-0982 also inhibited the expression and secretion of IL-4 and TNF-α in mast cells. Furthermore, CAC-0982 suppressed the mast cell-mediated allergic responses in mice in a dose-dependent manner (ED50 27.9mg/kg). As for the mechanism, CAC-0982 largely suppressed the phosphorylation of Syk and its downstream signaling molecules, including LAT, Akt, Erk1/2, p38, and JNK. Notably, the tyrosine kinase assay of antigen-stimulated mast cells showed that CAC-0982 inhibited Fyn kinase, one of the upstream tyrosine kinases for Syk activation in mast cells. Taken together, these results suggest that CAC-0982 may be used as a new treatment for regulating IgE-mediated allergic diseases through the inhibition of the Fyn/Syk pathway in mast cells.
authors.affiliation: Department of Immunology, School of Medicine, Konkuk University, Chungju 380-701, Republic of Korea; College of Medicine, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Jun Ho
authors.initials: JH
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Tae Hyung
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Department of Immunology, School of Medicine, Konkuk University, Chungju 380-701, Republic of Korea.
authors.forename: Hyuk Soon
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Immunology, School of Medicine, Konkuk University, Chungju 380-701, Republic of Korea.
authors.forename: A-Ram
authors.initials: AR
authors.lastname: Kim
authors.affiliation: Department of Immunology, School of Medicine, Konkuk University, Chungju 380-701, Republic of Korea; Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Do-Kyun
authors.initials: DK
authors.lastname: Kim
authors.affiliation: Department of Immunology, School of Medicine, Konkuk University, Chungju 380-701, Republic of Korea.
authors.forename: Seung Taek
authors.initials: ST
authors.lastname: Nam
authors.affiliation: Department of Immunology, School of Medicine, Konkuk University, Chungju 380-701, Republic of Korea.
authors.forename: Hyun Woo
authors.initials: HW
authors.lastname: Kim
authors.affiliation: Department of Immunology, School of Medicine, Konkuk University, Chungju 380-701, Republic of Korea.
authors.forename: Young Hwan
authors.initials: YH
authors.lastname: Park
authors.affiliation: Department of Immunology, School of Medicine, Konkuk University, Chungju 380-701, Republic of Korea.
authors.forename: Erk
authors.initials: E
authors.lastname: Her
authors.affiliation: Department of Immunology, School of Medicine, Konkuk University, Chungju 380-701, Republic of Korea.
authors.forename: Yeong Min
authors.initials: YM
authors.lastname: Park
authors.affiliation: College of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Hyung Sik
authors.initials: HS
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Duksung Women's University, Seoul 132-714, Republic of Korea.
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Kim
authors.affiliation: Department of Immunology, School of Medicine, Konkuk University, Chungju 380-701, Republic of Korea. Electronic address: wahnchoi@kku.ac.kr.
authors.forename: Wahn Soo
authors.initials: WS
authors.lastname: Choi
mesh_terms: D000818:Animals; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy / Q000276:immunology; D007073:Immunoglobulin E / Q000276:immunology*; D007211:Indoles / Q000494:pharmacology*; D015847:Interleukin-4 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects*; D051379:Mice; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C000599772:CAC-0982; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007073:Immunoglobulin E; C034082:indoxyl; D011505:Protein-Tyrosine Kinases; D051076:Proto-Oncogene Proteins c-fyn; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse
keywords: 5-Bromo-4-chloro-3-indolyl 1,3-diacetate CAC-0982; Allergy; Fyn kinase; Mast cells; Syk kinase