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| Status |
Public on Nov 03, 2011 |
| Title |
Interferon-alpha mediates the development of autoimmunity by direct tissue toxicity and through immune-cell recruitment mechanisms |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Interferon-alpha is a major therapeutic agent for many diverse diseases. However, the interferon-alpha mechanism of therapeutic action and associated side effects are not well understood. In particular, thyroiditis is a common unexplained complication. We hypothesized that direct thyroid-toxic actions coupled with immune mechanisms play a major role in the thyroiditis etiology. To test this hypothesis, we investigated the actions of interferon-alpha on cultured thyrocytes in vitro, and in vivo by creating transgenic mice overexpressing interferon-alpha tissue specifically in thyrocytes. Interferon-alpha treatment of cultured PCCL3 rat thyrocytes increased markers of thyroid differentiation, levels of MHC class I, and expression of heat shock protein and CXCL10. This was associated with markedly increased nonapoptotic thyroid cell death. Consistent with these in vitro findings, transgenic mice overexpressing interferon-alpha in the thyroid displayed striking thyroid cell death characteristic of nonimmune thyroid destruction that progressed to profound primary hypothyroidism. Moreover, genes linked to cell death pathways, granzyme B, or known to be associated with recruitment of a cytotoxic immune response, CXCL10, interleukin-23, and TRIM21 were increased in the transgenic thyroids. Taken together, the etiology of interferon-induced thyroiditis likely involves both a direct toxic action on thyrocytes, as well as provocation of a destructive immune response.
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| Overall design |
1) Thyroid cells were incubated with interferon-alpha, and global gene expression was determined by RNA-seq. 2) Thyroid tissues were obtained from transgenic mice overexpressing interferon-alpha and from wild type mice, and global gene expression was analyzed using RNA-seq.
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| Contributor(s) |
Akeno N, Smith EP, Huber AK, Stefan M, Zhang W, Keddache M, Tomer Y |
| Citation(s) |
21402899 |
| Submission date |
Nov 03, 2010 |
| Last update date |
May 15, 2019 |
| Contact name |
Weijia Zhang |
| E-mail(s) |
weijia.zhang@mssm.edu
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| Phone |
212-241-2883
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| Organization name |
Mount Sinai School of Medicine
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| Department |
Department of Medicine
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| Lab |
Bioinformatics Lab
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| Street address |
1425 Madison Avenue
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| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10029 |
| Country |
USA |
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| Platforms (2) |
| GPL10999 |
Illumina Genome Analyzer IIx (Homo sapiens) |
| GPL11002 |
Illumina Genome Analyzer IIx (Mus musculus) |
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| Samples (5)
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| Relations |
| SRA |
SRP005396 |
| BioProject |
PRJNA134511 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE25115_RAW.tar |
120.8 Mb |
(http)(custom) |
TAR (of BED, TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
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