| Fragments of Genomic DNA Released by Injured Cells Activate Innate Immunity and Suppress Endocrine Function in the Thyroid. | |
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MedLine Citation:
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PMID: 21303947 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Activation of innate and acquired immune responses, which can be induced by infection, inflammation, or tissue injury, may impact the development of autoimmunity. Although stimulation of cells by double-stranded DNA (dsDNA) has been shown to activate immune responses, the role of self-genomic DNA fragments released in the context of sterile cellular injury is not well understood. Using cultured thyroid cells, we show that cell injury prompts the release of genomic DNA into the cytosol, which is associated with the production of type I interferons, inflammatory cytokines, and chemokines. Molecules necessary for antigen processing and presentation to lymphocytes are also induced in thyroid cells by injury. dsDNA strongly suppressed the expression of sodium/iodide symporter and radioiodine uptake. To identify molecules responsible for sensing cytosolic dsDNA, we directly identified the cellular proteins that bound a dsDNA Sepharose column by mass spectrometry. Our analysis identified histone H2B, which was previously demonstrated to be an essential factor that mediates the activation of innate immunity induced by dsDNA. Knockdown of histone H2B using specific small interfering RNA abolished cell injury-induced innate immune activation and increased sodium/iodide symporter expression. These results indicate that genomic DNA fragments released by cell injury are recognized by extrachromosomal histone H2B, which results in the activation of genes involved in both innate and acquired immune responses in thyroid cells and suppression of thyroid function. These results suggest that sterile thyroid injury, in the absence of infection, may be sufficient to trigger autoimmune reaction and to induce thyroid dysfunction. |
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Authors:
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Akira Kawashima; Kazunari Tanigawa; Takeshi Akama; Huhehasi Wu; Mariko Sue; Aya Yoshihara; Yuko Ishido; Kouji Kobiyama; Fumihiko Takeshita; Ken J Ishii; Hisashi Hirano; Hiroaki Kimura; Takafumi Sakai; Norihisa Ishii; Koichi Suzuki |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-2-8 |
Journal Detail:
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Title: Endocrinology Volume: - ISSN: 1945-7170 ISO Abbreviation: - Publication Date: 2011 Feb |
Date Detail:
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Created Date: 2011-2-9 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0375040 Medline TA: Endocrinology Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Laboratory of Molecular Diagnostics (A.K., K.T., T.A., H.W., M.S., A.Y., Y.I., K.S.), Department of Mycobacteriology, Leprosy Research Center, National Institute of Infectious Diseases, Tokyo 189-0002, Japan; Department of Molecular Biodefense Research (K.K., F.T.), Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; Laboratory of Adjuvant Innovation (K.K., K.J.I.), Department of Fundamental Research, National Institute of Biomedical Innovation, Osaka 567-0085, Japan; International Graduate School of Arts and Sciences (H.H.), Yokohama City University, Yokohama 230-0045, Japan; Area of Regulatory Biology (A.K., T.S.), Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan; Division of Bioimaging Sciences (H.K.), Center for Molecular Medicine, Jichi Medical University, Shimotsuke 329-0498, Japan; and Leprosy Research Center (N.I.), National Institute of Infectious Diseases, Tokyo 189-0002, Japan. |
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