title: GM-CSF and IL-4 induce dendritic cell differentiation and disrupt osteoclastogenesis through M-CSF receptor shedding by up-regulation of TNF-alpha converting enzyme (TACE).
abstract: Monocytes give rise to macrophages, osteoclasts (OCs), and dendritic cells (DCs). Macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kappaB (RANK) ligand induce OC differentiation from monocytes, whereas granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) trigger monocytic differentiation into DCs. However, regulatory mechanisms for the polarization of monocytic differentiation are still unclear. The present study was undertaken to clarify the mechanism of triggering the deflection of OC and DC differentiation from monocytes. GM-CSF and IL-4 abolished monocytic differentiation into OCs while inducing DC differentiation even in the presence of M-CSF and RANK ligand. GM-CSF and IL-4 in combination potently up-regulate tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE) and activity in monocytes, causing ectodomain shedding of M-CSF receptor, resulting in the disruption of its phosphorylation by M-CSF as well as the induction of osteoclastogenesis from monocytes by M-CSF and RANK ligand. Interestingly, TACE inhibition robustly causes the resumption of the surface expression of M-CSF receptor on monocytes, facilitating M-CSF-mediated phosphorylation of M-CSF receptor and macrophage/OC differentiation while impairing GM-CSF- and IL-4-mediated DC differentiation from monocytes. These results reveal a novel proteolytic regulation of M-CSF receptor expression in monocytes to control M-CSF signaling and monocytic differentiation into macrophage/OC-lineage cells or DCs.
authors.affiliation: Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medical Sciences, Tokushima, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hiasa
authors.forename: Masahiro
authors.initials: M
authors.lastname: Abe
authors.forename: Ayako
authors.initials: A
authors.lastname: Nakano
authors.forename: Asuka
authors.initials: A
authors.lastname: Oda
authors.forename: Hiroe
authors.initials: H
authors.lastname: Amou
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Kido
authors.forename: Kyoko
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Kumiko
authors.initials: K
authors.lastname: Kagawa
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Yata
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Shuji
authors.initials: S
authors.lastname: Ozaki
authors.forename: Kenzo
authors.initials: K
authors.lastname: Asaoka
authors.forename: Eiji
authors.initials: E
authors.lastname: Tanaka
authors.forename: Keiji
authors.initials: K
authors.lastname: Moriyama
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsumoto
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D053245:RANK Ligand; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human