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Blood, 1 December 2008, Vol. 112, No. 12, pp. 4699-4711. Prepublished online as a Blood First Edition Paper on September 17, 2008; DOI 10.1182/blood-2008-01-137018. This Article Full Text (PDF) Supplemental Methods, Tables, and Figure All Versions of this Article: blood-2008-01-137018v1 112/12/4699    most recent Alert me when this article is cited Alert me if a correction is posted 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 Citing Articles via Google Scholar Google Scholar Articles by Shi, C. Articles by Simon, D. I. Search for Related Content PubMed PubMed Citation Articles by Shi, C. Articles by Simon, D. I. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 31, 2008 Accepted August 22, 2008 Downregulation of the forkhead transcription factor Foxp1 is required for monocyte differentiation and macrophage function Can Shi, Masashi Sakuma, Toshifumi Mooroka, Alison Liscoe, Huiyun Gao, Kevin J. Croce, Arjun Sharma, David Kaplan, David R. Greaves, Yunmei Wang, and Daniel I. Simon* Department of Medicine, Case Cardiovascular Center, Case Western Reserve University School of Medicine, Cleveland, OH, United States Department of Pathology, Case Cardiovascular Center, Case Western Reserve University School of Medicine, Cleveland, OH, United States Molecular Pathology, Sir William Dunn School of Pathology, Oxford, United Kingdom University Hospitals Harrington-McLaughlin Heart & Vascular Institute, Cleveland, OH, United States * Corresponding author; email: daniel.simon{at}uhhospitals.org. Downregulation of the forkhead transcription factor Foxp1 by integrin engagement controls monocyte differentiation in vitro. To determine whether Foxp1 plays a critical role in monocyte differentiation and macrophage functions in vivo, we generated transgenic mice (macFoxp1tg) over-expressing human Foxp1 in monocyte/macrophage lineage cells using the CD68 promoter. Circulating blood monocytes from macFoxp1tg mice have reduced expression of the receptor for macrophage colony-stimulating factor (c-fms/M-CSFR), impaired migratory capacity, and diminished accumulation as splenic macrophages. Macrophage functions, including cytokine production, phagocytosis, and respiratory burst were globally impaired in macFoxp1tg compared to wild-type cells. Osteoclastogenesis and bone resorption activity were also attenuated in macFoxp1tg mice. In models of chemical and bacterial peritonitis, macFoxp1tg mice exhibited reduced macrophage accumulation, bacterial clearance, and survival. Enforced overexpression of c-fms/M-CSFR reversed the cytokine production and phagocytosis defects in macFoxp1tg macrophages, indicating that repression of c-fms/M-CSFR is likely the dominant mechanism responsible Foxp1 action in monocyte differentiation and macrophage function. Taken together, these observations identify downregulation of Foxp1 as critical for monocyte differentiation and macrophage functions in vivo. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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