Masato Asai

Background: Iodide that is essential for thyroid hormone synthesis is actively transported into the thyroid follicular cells via sodium/iodide symporter (NIS) protein in vertebrates. It is well known that NIS expression in thyroid is regulated by the thyroid statuses mainly through thyroid stimulating hormone (TSH). AlthoughNISmRNA expressions in extrathyroidal tissues have been qualitatively reported, their regulation by thyroid statuses has not been well clarified.Methods: Male ICR mice aged four weeks were assigned into three groups (control, hypothyroid, and hyperthyroid). Hypothyroid group of mice were treated with 0.02% methimazole in drinking water and hyperthyroid group of mice received intraperitoneal injection (4 μg_L-T₄twice a week) for four weeks.NISmRNA expression levels in the tissues were evaluated using Northern blot hybridization and quantitative real-time RTPCR (qPCR). Additionally, end-point RTPCR for the thyroid follicular cell-characteristic genes (TSH receptor,TSHR; thyroid transcription factor-1,TTF1; and paired box gene 8,Pax8) was carried out.Results: By Northern blot analysis,NISmRNA was detected in thyroid and stomach. In addition to these organs, qPCR revealed the expression also in the submandibular gland, colon, testis, and lung. Expression ofNISmRNA in thyroid was significantly increased in hypothyroid and decreased in hyperthyroid group. Trends ofNISmRNA expression in extrathyroidal tissues were not in line with that in the thyroid gland in different thyroid statuses. Only in lung,NISmRNA was regulated by thyroid statuses but in opposite way compared to the manner in the thyroid gland. There were no extrathyroidal tissues that expressed all three characteristic genes of thyroid follicular cells.Conclusions: NISmRNA expression in the thyroid gland was up-regulated in hypothyroid mice and was down-regulated in hyperthyroid mice, suggesting thatNISmRNA in the thyroid gland is regulated by thyroid statuses. In contrast,NISmRNA expression in extrathyroidal tissues was not altered by thyroid statuses although it was widely expressed. Lack of responsiveness ofNISmRNA expressions in extrathyroidal tissues reemphasizes additional functions of NIS protein in extrathyroidal tissues other than iodide trapping.

Rosalyn Yalow, the inventor of radioimmunoassay, found that insulin treatments led to the production of antibodies against insulin.¹ Initially, this phenomenon was thought to be due to slight immunogenicity induced by the refining of preparations or the difference in amino acid sequences between species. However, even today, when genetically engineered preparations of human insulin are used, anti–human insulin IgG subclasses still are frequently detected in patients treated with insulin. Why therapeutically used insulin molecules, despite having exactly the same primary structure as endogenous insulin, are immunogenic has not been fully clarified.

The presence of high-affinity binding sites for antidiabetic sulfonylureas (SUs) and the expression of SU receptor (SUR) messenger RNA in the adenohypophyseal cells have recently been reported. In this study, we examined the effects of SU on POMC gene expression and ACTH secretion using the AtT20PL cell line, a subclone of AtT20 in which the rat POMC 5′-promoter-luciferase fusion gene was stably incorporated. A representative SU glibenclamide inhibited the basal POMC 5′-promoter activity. In contrast, glibenclamide enhanced forskolin- or CRH-induced POMC expression in a dose-dependent manner. Interestingly, the latter effect was not observed under treatment with 3-isobutyl-1-methylxanthine, a nonselective phosphodiesterase inhibitor. Furthermore, diazoxide, an opener of the ATP-sensitive K⁺ channel, only antagonized the suppressive effect of glibenclamide. Lastly, RT-PCR analysis showed that mouse SUR (but not SUR2) messenger RNA was expressed in this cell line. These results suggest that, in AtT20PL cells, SU has dual effects, i.e. a suppressive effect on basal POMC expression through diazoxide-sensitive (ATP-sensitive) K⁺-channel-mediated mechanism, and an enhancing effect on cAMP/protein kinase A-stimulated POMC expression through a different mechanism (probably mediated by phosphodiesterase). To our knowledge, this is the first report showing the effect of SU on the expression of the anterior pituitary hormone gene.