TRH was initially found in the hypothalamus and regulates TSH secretion. TRH is also produced by insulincontaining -cells. Endogenous TRH positively regulates glucagon secretion and attenuates pancreatic exocrine secretion. We have previously shown that triiodothyronine (T 3 ) down-regulates pre-pro-TRH gene expression in vivo and in vitro. The present study was designed to determine the initial impact of T 3 on rat TRH gene promoter and to compare this effect with that of dexamethasone (Dex). Primary islet cells and neoplastic cells (HIT T-15 and RIN m5F) were transiently transfected with fragments of the 5 -flanking sequence of TRH fused to the luciferase reporter gene. The persistence of high TRH concentrations in fetal islets in culture, probably due to transactivating factors, allowed us to explore how T 3 and Dex regulate the TRH promoter activity in transfected cells and whether the hormone effect is dependent on the cell type considered. TRH gene promoter activity is inhibited by T 3 in primary but not neoplastic cells and stimulated by Dex in both primary and neoplastic cells of islets. These findings validate previous in vivo and in vitro studies and indicate the transcriptional impact of these hormones on TRH gene expression in the pancreatic islets.
TRH is localized with insulin in beta-cells. It is synthesized as a prohormone containing five copies of TRH and seven cryptic peptides, including pro (p)-TRH-(160-169). Thyroid hormone regulates the expression of several genes encoding peptide hormones. We found that circulating T3 concentrations were inversely correlated with TRH levels in two physiopathological situations. There are low concentrations of circulating thyroid hormone and very high concentrations of TRH and pTRH-(160-169) during development, and experimental hypothyroidism results in higher concentrations of prepro (pp)-TRH messenger RNA (mRNA) and TRH content in the adult rat pancreas than are present in the euthyroid pancreas. The present study was carried out to investigate the interaction between T3 and pancreatic TRH during the functional maturation of islets in culture and to validate the data obtained in vivo. T3 decreases ppTRH mRNA in islets in a dose-dependent manner. The primary impact of T3 on islet function may be mediated by ppTRH mRNA, as short term T3 treatment had no effect. Long term T3 treatment reduced the islet TRH content and the amounts of pTRH-(160-169) and insulin released. This secretory pattern and coordinated regulation of pTRH-(160-169) and insulin suggests that pTRH-(160-169) plays a specific role in the regulation of insulin secretion.
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