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Blood, 12 November 2009, Vol. 114, No. 20, pp. 4517-4526. Prepublished online as a Blood First Edition Paper on September 17, 2009; DOI 10.1182/blood-2009-04-215020. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2009-04-215020v1 114/20/4517    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Hiasa, M. Articles by Matsumoto, T. PubMed PubMed Citation Articles by Hiasa, M. Articles by Matsumoto, T. Related Collections Phagocytes, Granulocytes, and Myelopoiesis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PHAGOCYTES, GRANULOCYTES, AND MYELOPOIESIS GM-CSF and IL-4 induce dendritic cell differentiation and disrupt osteoclastogenesis through M-CSF receptor shedding by up-regulation of TNF- converting enzyme (TACE) Masahiro Hiasa13, Masahiro Abe1, Ayako Nakano1, Asuka Oda1, Hiroe Amou1, Shinsuke Kido1, Kyoko Takeuchi1, Kumiko Kagawa1, Kenichiro Yata1, Toshihiro Hashimoto1, Shuji Ozaki1, Kenzo Asaoka2, Eiji Tanaka3, Keiji Moriyama4, and Toshio Matsumoto1 1 Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medical Sciences, Tokushima; 2 Department of Biomaterials and Bioengineerings, University of Tokushima Graduate School of Oral Sciences, Tokushima; 3 Department of Orthodontics and Dentofacial Orthopedics, University of Tokushima Graduate School of Oral Sciences, Tokushima; and 4 Department of Maxillofacial Orthognathics, Tokyo Medical and Dental University, Tokyo, Japan 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- (TNF-) 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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