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Comparison of gene expression in thyrocytes between wildtype and thyroid-specific IFNg transgenic mice

ABSTRACT: Hürthle cells are found in thyroid tumors and autoimmunity, and have a unique appearance characterized by swollen eosinophilic cytoplasm filled with mitochondria and hyperchromatic nucleus. The pathogenesis of Hürthle cells remains unknown. We have generated transgenic mice expressing IFNg specifically in thyroid gland, and shown they develop changes in the thyroid follicular cell that resemble those of the human Hürthle cell. Transcriptome analysis by serial analysis of gene expression revealed an increased expression of immunoproteasome subunits in transgenic thyrocytes. LMP2, an immunoproteasome subunit also known as PSMB9 or ib1, provided critical for Hürthle cells and hypothyroidism development. Transgenic mice treated with a proteasome inhibitor ameliorated the Hürthle cell phenotype, and failed to develop it when crossed to LMP2 deficient mice. LMP2 was expressed in Hürthle cells from Hashimoto thyroiditis and thyroidal cancer patients. We propose that LMP2 is a nobel therapeuetic target for Hürthle cell lesions.

ORGANISM(S): Mus musculus

PROVIDER: GSE15114 | GEO | 2009/07/01

SECONDARY ACCESSION(S): PRJNA114865

REPOSITORIES: GEO

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Project description:Although viral infection is thought to be associated with subacute thyroiditis and probably with autoimmune thyroid disease, possible changes in thyroid function during the prodromal period of infection or subclinical infection remain largely unknown. Recently, it was shown that pathogen-associated molecular patterns stimulate Toll-like receptors (TLR) and activate innate immune responses by producing type I interferons (IFN). Using a human thyroid follicle culture system, in which de novo synthesized thyroid hormones are released into the culture medium under physiological concentrations of hTSH, we studied the effects of polyinosinic-polycytidylic acid (Poly(I:C)), a chemical analog of viral double-stranded RNA (dsRNA), on TSH-induced thyroid function. Thyrocytes expressed ligands for dsRNA (TLR 3, CD14, and RIG-1) comparable to the TSH receptor. DNA microarray and real-time PCR analyses revealed that dsRNA increased the expression of mRNA for TLR3, IFN-g, interferon-regulating factors, proinflammatory cytokines, and class I MHC, whereas genes associated with thyroid hormonogenesis (NIS, peroxidase, deiodinases) were suppressed. In accordance to these data, Poly(I:C) suppressed TSH-induced 125I uptake and hormone synthesis dose-dependently, accompanied by a decrease in the ratio of 125I-T3/125I-T4 released into the culture medium, whereas peptidoglycan, lipopolysaccharides, or unmethylated CpG DNA, ligands for TLR2, TLR4, and TLR9, respectively, had no significant effect. These inhibitory effects of Poly(I:C) were not blocked by a neutralizing antibody against TLR3 and an anti-IFN alpha/beta receptor antibody. These in vitro findings suggest that when thyrocytes are infected with certain viruses, dsRNA formed intracellularly in thyrocytes may be a cause for thyroid dysfunction, leading to development of autoimmune thyroiditis. This data was published in Endocrinology, vol.148, 3226-3235, 2007. Experiment Overall Design: Two conditioned experimets, control vs. double-stranded RNA (polyI-C), cultured for 6

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Comparison of gene expression in thyrocytes between wildtype and thyroid-specific IFNg transgenic mice

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