| IFN-α mediates the development of autoimmunity both by direct tissue toxicity and through immune cell recruitment mechanisms. | |
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MedLine Citation:
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PMID: 21402899 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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IFN-α is known to play a key role in autoimmunity, but the mechanisms are uncertain. Although the induction of autoimmunity by IFN-α is consistent with primarily immunomodulatory effects, the high frequency of nonautoimmune inflammation suggests other mechanisms. We used thyroiditis as a model to dissect these possibilities. IFN-α treatment of cultured thyrocytes increased expression of thyroid differentiation markers, thyroglobulin, thyroid-stimulating hormone receptor, thyroid peroxidase, and sodium iodide transporter. RNAseq analysis demonstrated that pathways of Ag presentation, pattern recognition receptors, and cytokines/chemokines were also stimulated. These changes were associated with markedly increased nonapoptotic thyroid cell death, suggesting direct toxicity. To corroborate these in vitro findings, we created transgenic mice with thyroid-specific overexpression of IFN-α under control of the thyroglobulin promoter. Transgenic mice developed marked inflammatory thyroid destruction associated with immune cell infiltration of thyroid and surrounding tissues leading to profound hypothyroidism, findings consistent with our in vitro results. In addition, transgenic mice thyroids showed upregulation of pathways similar to those observed in cultured thyrocytes. In particular, expression of granzyme B, CXCL10, a subset of the tripartite motif-containing family, and other genes involved in recruitment of bystander cytotoxic immune responses were increased. Pathways associated with apoptosis and autophagy were not induced. Taken together, our data demonstrate that the induction of tissue inflammation and autoimmunity by IFN-α involves direct tissue toxic effects as well as provocation of destructive bystander immune responses. |
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Authors:
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Nagako Akeno; Eric P Smith; Mihaela Stefan; Amanda K Huber; Weijia Zhang; Mehdi Keddache; Yaron Tomer |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. Date: 2011-03-14 |
Journal Detail:
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Title: Journal of immunology (Baltimore, Md. : 1950) Volume: 186 ISSN: 1550-6606 ISO Abbreviation: J. Immunol. Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-04-05 Completed Date: 2011-08-01 Revised Date: 2012-04-18 |
Medline Journal Info:
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Nlm Unique ID: 2985117R Medline TA: J Immunol Country: United States |
Other Details:
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Languages: eng Pagination: 4693-706 Citation Subset: AIM; IM |
Affiliation:
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Division of Endocrinology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Autoimmunity / immunology* Cell Line Cells, Cultured Dose-Response Relationship, Drug Female Gene Expression / drug effects Gene Expression Profiling Humans Immune System / cytology, immunology*, metabolism Interferon-alpha / genetics, immunology*, pharmacology Leukocytes, Mononuclear / cytology, immunology, metabolism Male Mice Mice, Inbred C57BL Mice, Inbred CBA Mice, Transgenic Rats Receptor, Interferon alpha-beta / genetics Reverse Transcriptase Polymerase Chain Reaction Thyroid Gland / cytology, immunology*, metabolism Thyroiditis / genetics, metabolism Time Factors |
| Grant Support | |
ID/Acronym/Agency:
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DK073681/DK/NIDDK NIH HHS; DK61659/DK/NIDDK NIH HHS; R01 DK061659-08/DK/NIDDK NIH HHS; R01 DK073681-04/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Interferon-alpha; 156986-95-7/Receptor, Interferon alpha-beta |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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