HPT axis‑independent TSHβ splice variant regulates the synthesis of thyroid hormone in mice

Abstract

Thyroid stimulating hormone (TSH) consists of an α-subunit and a unique β-subunit. The first in-frame TSHβ splice variant produced by the cells of immune system was identified in 2009. The TSHβ splice variant and native TSHβ exhibit different expression profiles, and research has been conducted to elucidate the role of the TSHβ splice variant in different diseases. However, understanding of the fundamental physiological characteristics of the TSHβ splice variant is currently limited. To verify whether the TSHβ splice variant has the potential to induce thyroid follicular cells to synthesize thyroid hormone, in vivo and in vitro stimulation experiments were conducted in the present study. A total of 60 C57BL/6 mice were divided into control-, 5 and 10 µg TSHβ splice variant-treated groups at random. Mice were sacrificed at 0.5, 1 and 4 h after intraperitoneal injection, and serum levels of tri-iodothyronine (T3) and thyroxine (T4) were determined using a radioimmunoassay. Thyroid follicular cells were isolated from the thyroids of mice, and stimulated with 2 µg/ml TSHβ splice variant. Supernatants were collected, and the levels of T3 and T4 were detected. The protein expression levels of the sodium-iodide symporter, thyroperoxidase and thyroglobulin in thyroid follicular cells were quantified using western blot analysis. To verify whether the TSHβ splice variant expression was regulated by the hypothalamus-pituitary-thyroid (HPT) axis, similar to native TSHβ, a total of 60 C57BL/6 mice were equally divided into control, 2 mg/kg T3 intraperitoneal injection and 0.05 mg/kg thyroid-releasing hormone intraperitoneal injection groups at random. Mice were sacrificed at 1 and 4 h after injection. Alterations in the expression of the TSHβ splice variant in the pituitary, thyroid, peripheral blood leukocytes and spleen tissues were detected using western blot analysis. The present study demonstrated that the TSHβ splice variant is not regulated by the HPT axis and may affect thyroid hormone synthesis. Modifications in the expression of the TSHβ splice variant may occur in a uniquely regulated manner to provide peripheral immunological compartments with a source of activated cells, particularly under immune stress.

Peripubertal soy isoflavone consumption leads to subclinical hypothyroidism in male Wistar rats

“…In autoimmune thyroiditis, especially Hashimoto's thyroiditis, high levels of Tshbv in peripheral blood leukocytes were identified 63 . This Tshbv is able to induce the synthesis of THs independently of the regulation of the HP thyroid axis 64 .…”

Independent Skeletal Actions of Pituitary Hormones

“…Interestingly, the regulation of TSH-βv does not follow traditional hypothalamic-pituitary-thyroid axis feedback. TSH-βv injection into mice increases serum T4/T3 levels, but TSH-βv expression in leukocytes was not increased or suppressed in response to thyrotropin releasing hormone (TRH) or T3, respectively [89]. Also, T4/T3 regulated TSH-βv expression positively at mRNA and protein levels rather than suppressing it [87,90].…”

Dynamic Interactions Between the Immune System and the Neuroendocrine System in Health and Disease

“…Moreover, TSHβv has been shown to induce TH synthesis in vivo and in vitro . T3 and T4 were elevated in the circulation of mice within one hour of injection of recombinant TSHβv, and to induce the secretion of T3 and T4 from thyroid follicular cells in vitro ( 44 ). What’s more, levels of thyroglobulin, thyroid peroxidase, and sodium-iodide supporter were elevated in thyroid follicular cells following TSHβv stimulation.…”

“…What’s more, levels of thyroglobulin, thyroid peroxidase, and sodium-iodide supporter were elevated in thyroid follicular cells following TSHβv stimulation. Of particular interest, injection of mice with T3 and TRH caused a transient drop followed by an increase in native TSHβ though not in TSHβv in the pituitary ( 44 ).…”

“…Additionally, TSHβv-producing plasma cells infiltrated the thyroid in HT patients ( 40 ). Recent studies demonstrate that immune system TSHβv in humans operates independently of the HPT axis and is capable of inducing TH synthesis from PBL in times of immune stress, such as during systemic infection ( 44 ). Those possibility conforms to finding in mice showing that TSHβv-producing inflammatory cells traffic to the thyroid following L. monocytogenes infection ( 38 ).…”