title: Eosinophilic differentiation is promoted by blockage of Notch signaling with a gamma-secretase inhibitor.
abstract: Although increasing evidence supports the inhibitory role of Notch in granulocyte differentiation, the direct effects of Notch on the differentiation and maturation of eosinophils, one type of granulocyte, have not yet been studied. We investigated whether a blockage of Notch signaling promoted the differentiation of eosinophils from umbilical cord blood (UCB) cells. Freshly isolated UCB cells were cultured with IL-3, IL-5 and GM-CSF in the presence or absence of a gamma-secretase inhibitor L-685,458, and examined for the expression of major basic protein (MBP). Freshly isolated UCB cells expressed mRNA and proteins for Notch 1, Notch 2, Delta 1, and Jagged 1. MBP expression in cultures with the inhibitor was significantly increased, as compared with the cultures in the absence of the inhibitor. Treatment with the inhibitor was accompanied by a decrease in Hes 1 mRNA expression, indicative of Notch-mediated signaling for the inhibitor effect. UCB cells cultured with the inhibitor for 28 days displayed similar levels of CCR3, a late marker of eosinophil development, as compared with the cells cultured without the inhibitor, but almost completely lost chemotaxis response to eotaxin. Our data suggest that Notch signaling may modulate eosinophil migration at the mature stage as well as inhibit eosinophil differentiation.
authors.affiliation: Division of Molecular and Life Sciences, College of Science and Technology, Hanyang University, Ansan, South Korea.
authors.forename: Jin Hyun
authors.initials: JH
authors.lastname: Kang
authors.forename: Da Hye
authors.initials: DH
authors.lastname: Lee
authors.forename: Jong Soo
authors.initials: JS
authors.lastname: Lee
authors.forename: Hai Joong
authors.initials: HJ
authors.lastname: Kim
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Shin
authors.forename: Young Han
authors.initials: YH
authors.lastname: Lee
authors.forename: Young Seek
authors.initials: YS
authors.lastname: Lee
authors.forename: Choon-Sik
authors.initials: CS
authors.lastname: Park
authors.forename: Il Yup
authors.initials: IY
authors.lastname: Chung
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D051792:Basic Helix-Loop-Helix Proteins / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002219:Carbamates / Q000494:pharmacology; D016923:Cell Death / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D004151:Dipeptides / Q000494:pharmacology; D010450:Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D047093:Eosinophil Major Basic Protein / Q000276:immunology; D004804:Eosinophils / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D012333:RNA, Messenger / Q000032:analysis; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072056:Transcription Factor HES-1
chemical_list: D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D051792:Basic Helix-Loop-Helix Proteins; D002219:Carbamates; D004151:Dipeptides; D010450:Endopeptidases; D004791:Enzyme Inhibitors; D047093:Eosinophil Major Basic Protein; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D000072056:Transcription Factor HES-1; C515350:CCR3 protein, human; C410009:L 685458; C078493:HES1 protein, human; C509280:BACE1 protein, human