Unknown,Transcriptomics,Genomics,Proteomics

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Interferon-alpha mediates the development of autoimmunity by direct tissue toxicity and through immune-cell recruitment mechanisms

ABSTRACT: 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. 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.

ORGANISM(S): Mus musculus

SUBMITTER: Weijia Zhang

PROVIDER: E-GEOD-25115 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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IFN-α mediates the development of autoimmunity both by direct tissue toxicity and through immune cell recruitment mechanisms.

Akeno Nagako N Smith Eric P EP Stefan Mihaela M Huber Amanda K AK Zhang Weijia W Keddache Mehdi M Tomer Yaron Y

Journal of immunology (Baltimore, Md. : 1950) 20110314 8

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 ...[more]

PMID: 21402899

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Interferon-alpha mediates the development of autoimmunity by direct tissue toxicity and through immune-cell recruitment mechanisms

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IFN-α mediates the development of autoimmunity both by direct tissue toxicity and through immune cell recruitment mechanisms.

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