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Nishi-Tokyo-shi, Japan

Kawashima A.,Japan National Institute of Infectious Diseases | Yamazaki K.,Thyroid Disease Institute | Hara T.,Japan National Institute of Infectious Diseases | Akama T.,Japan National Institute of Infectious Diseases | And 9 more authors.
Thyroid | Year: 2013

Background: Autoimmune thyroid disease is an archetypal organ-specific autoimmune disorder that is characterized by the production of thyroid autoantibodies and lymphocytic infiltration into the thyroid. However, the underlying mechanisms by which specific thyroid antibodies are produced are largely unknown. Recent studies have shown that innate immune responses affect both the phenotype and the severity of autoimmune reactions. Moreover, it appears that even non-immune cells, including thyroid cells, have an ability to launch such responses. The aim of this study was to conduct a more detailed analysis of innate immune responses of the thyroid upon stimulation with various "non-self" and "self" factors that might contribute to the initiation of autoimmune reactions. Methods: We used rat thyroid FRTL-5 cells, human thyroid cells, and mice to investigate the effects of various pathogen-Associated molecular patterns (PAMPs), danger-Associated molecular patterns (DAMPs), and iodide on gene expression and function that were related to innate immune responses. Results: RT-PCR analysis showed that both rat and human thyroid cells expressed mRNAs for Toll-like receptors (TLRs) that sensed PAMPs. Stimulation of thyrocytes with TLR ligands resulted in activation of the interferon-beta (IFN-β) promoter and the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB)-dependent promoter. As a result, pro-inflammatory cytokines, chemokines, and type I interferons were produced. Similar activation was observed when thyroid cells were stimulated with double-stranded DNA, one of the typical DAMPs. In addition to these PAMPs and DAMPs, treatment of thyroid cells with high concentrations of iodide increased mRNA expression of various cytokines. Conclusion: We show that thyroid cells express functional sensors for exogenous and endogenous dangers, and that they are capable of launching innate immune responses without the assistance of immune cells. Such responses may relate to the development of thyroiditis, which in turn may trigger autoimmune reactions. © Copyright 2013, Mary Ann Liebert, Inc. 2013.

Yamazaki K.,Thyroid Disease Institute | Tanigawa K.,Japan National Institute of Infectious Diseases | Suzuki K.,Japan National Institute of Infectious Diseases | Yamada E.,Thyroid Disease Institute | And 4 more authors.
Thyroid | Year: 2010

Background: It is well known that iodide exacerbates thyroid function in subclinical hypothyroid patients with autoimmune thyroiditis. To investigate the immunological mechanism of iodine-induced thyroid dysfunction, we studied the effect of iodide in cultured human thyroid follicles, which respond to physiological concentrations of human thyrotropin (TSH) (0.3-10μU/mL) and maintain the Wolff-Chaikoff effect. Materials and Methods: Thyroid follicles obtained from Graves' patients at subtotal thyroidectomy were precultured in medium containing 0.5% fetal calf serum and 10-8 M iodide for 5 days, and then cultured with the medium containing bovine TSH (30μU/mL) and low (10-8M) or high (10-5M) concentrations of iodide. After 3-72 hours of culture, the effect of iodide on thyroid cell mRNA expression was analyzed by microarray and reverse transcriptase-polymerase chain reaction. Results: After 48 hours of culture, iodide nearly doubled the mRNA expression levels of the immunity-associated genes (intercellular adhesion molecule-1, transforming growth factor beta 1-induced protein, early growth response gene 1, guanylate-binding protein 1, and annexin A1) and decreased the mRNA expression of sodium-iodide symporter to less than 20%. Further, the mRNA expression levels of chemokines (CCL2, CXCL8, and CXCL14) increased nearly twofold, whereas their receptors did not show any significant response. Real-time polymerase chain reaction analyses confirmed that iodide increased the mRNA expression levels of these genes in a time- and concentration-dependent manner. Immunohistochemical studies revealed that the chemokines were expressed mainly in the thyroid follicular cells in addition to the immune cells. The iodide-induced increase in CCL2 was greater in thyroid follicles obtained from thyroid gland that had been moderately infiltrated with the immunocompetent cells. Conclusion: We have demonstrated that iodide stimulates thyroid follicular cells to produce chemokines, particularly CCL2, CXCL8, and CXCL14. These chemokines and intercellular adhesion molecule-1 would attract immunocompetent cells into thyroid gland. These in vitro findings suggest that iodide at high concentrations may induce thyroid dysfunction through not only biochemical but also immunological mechanisms, particularly in patients with autoimmune thyroid disorders. © Mary Ann Liebert, Inc.

Ishido Y.,Japan National Institute of Infectious Diseases | Yamazaki K.,Thyroid Disease Institute | Kammori M.,Thyroid Disease Institute | Sugishita Y.,Thyroid Disease Institute | And 5 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Context: It was shown in the rat thyroid that thyroglobulin (Tg) stored in the follicular lumen is a potent regulator of thyroid-specificgeneexpression to maintain the function of individual follicles. However, the actions of Tg as a regulatory molecule in human thyroid have not been studied. Objective: Our objective was to determine the effect of Tg on gene expression in normal and diseased human thyroid and to examine whether the proposed model of negative-feedback autocrine regulation of thyroid function by Tg is applicable in the human as well as the rat. Design: Primary cultures of human thyrocytes were established from normal thyroid, Graves' disease thyroid, adenomatous goiter, follicular adenoma, and papillary carcinoma tissues obtained during surgery. Cells were stimulated with physiologic (ie, follicular) concentrations of Tg, and mRNA and protein expression of genes involved in thyroid hormonogenesis were evaluated. The effects of Tg on thyroid-specific gene expression were also assessed in 2 human papillary carcinoma cell lines. Results: Transcript levels of genes participating in thyroid hormone biosynthesis were significantly reduced by Tg in thyrocyte cultures derived from normal and Graves' thyroid, but not in cultures derived from thyroid neoplasms and adenomatous goiter. Conclusion: It was confirmed that Tg acts as a negative-feedback regulator of gene expression in human thyrocytes, suggesting that Tg signaling may constitute a common mechanism for maintaining thyroid homeostasis in species with follicular thyroid morphology. However, certain diseases of intrinsic thyroid overgrowth appear to be associated with an escape from the regulatory mechanism of Tg. Copyright © 2014 by the Endocrine Society.

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