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Blood, 8 October 2009, Vol. 114, No. 15, pp. 3244-3254. Prepublished online as a Blood First Edition Paper on June 30, 2009; DOI 10.1182/blood-2009-04-217620. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2009-04-217620v1 114/15/3244    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 HighWire Citing Articles via CrossRef Google Scholar Articles by Ishii, M. Articles by Kunkel, S. L. PubMed PubMed Citation Articles by Ishii, M. Articles by Kunkel, S. L. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 21, 2009 Accepted June 22, 2009 Epigenetic regulation of the alternatively activated macrophage phenotype Makoto Ishii, Haitao Wen, Callie A.S. Corsa, Tianju Liu, Ana L. Coelho, Ronald M. Allen, William F. Carson IV, Karen A. Cavassani, Xiangzhi Li, Nicholas W. Lukacs, Cory M. Hogaboam, Yali Dou, and Steven L. Kunkel* Immunology Program, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, United States Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, United States * Corresponding author; email: slkunkel{at}umich.edu. Alternatively activated (M2) macrophages play critical roles in diverse chronic diseases, including parasite infections, cancer, and allergic responses. However, little is known about the acquisition and maintenance of their phenotype. We report that M2-macrophage marker genes are epigenetically regulated by reciprocal changes in histone H3 lysine-4 (H3K4) and histone H3 lysine-27 (H3K27) methylation; and the latter methylation marks are removed by the H3K27 demethylase Jumonji domain containing 3 (Jmjd3). We found that continuous IL-4 treatment leads to decreased H3K27 methylation, at the promoter of M2 marker genes, and a concomitant increase in Jmjd3 expression. Furthermore, we demonstrate IL-4-dependent Jmjd3 expression is mediated by STAT6, a major transcription factor of IL-4-mediated signaling. After IL-4-stimulation, activated STAT6 is increased and binds to consensus sites at the Jmjd3 promoter. Increased Jmjd3 contributes to the decrease of H3K27 di- and tri-methylation (H3K27me2/3) marks as well as the transcriptional activation of specific M2 marker genes. The decrease in H3K27me2/3 and increase in Jmjd3 recruitment was confirmed by in vivo studies using a Schistosoma mansoni egg-challenged mice model; a well studied system known to support an M2 phenotype. Collectively, these data indicate that chromatin remodeling is mechanistically important in the acquisition of the M2-macrophage phenotype. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Orchestration of macrophage polarization Alberto Mantovani and Massimo Locati Blood 2009 114: 3135-3136. [Abstract] [Full Text] [PDF] This article has been cited by other articles: A. Mantovani and M. Locati Orchestration of macrophage polarization Blood, October 8, 2009; 114(15): 3135 - 3136. [Abstract] [Full Text] [PDF]

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