Thyrotropin releasing hormone and its cyclised C-terminal peptide inhibit thyroglobulin release from thyroid follicular cells: evidence for acute regulation of hormone production at the thyroid gland

Abstract

Purpose: Thyrotropin releasing hormone (TRH), a tripeptide hormone produced in the hypothalamus, controls thyroid stimulating hormone (TSH) production from the pituitary gland and hence the production of thyroid hormone. Extra-hypothalamic production and action of TRH has been detected, as has the presence of a C-terminal cyclised derivative, histidyl-proline diketopiperazine (His-Pro DKP). This study investigates the effects of these compounds on thyroglobulin release from thyroid follicular cells. Methods: DKPs were identified by chromatography and mass spectrometry. Expression of RNAs and proteins were identified in the FTRL-5 thyroid cell line and supernatant using RT-qPCR and immunoblotting. Results: We show that TRH is expressed by rat follicular thyroid cells, as is Pgpep1, the enzyme required for removal of the N-terminal amino acid of TRH. The rate of His-Pro DKP production from the C-terminal dipeptide of TRH is enhanced by thyroid extract in vitro. Both TRH and His-Pro DKP reduce thyroglobulin release from thyroid follicular cells with the magnitude of this effect attenuated in the presence of TSH, which also inhibits the expression of Pgpep1. Conclusion: Collectively, these data indicate that TRH and its cyclised dipeptide derivative directly regulate thyroid production within the thyroid gland, potentially in a manner dependent upon the activity of the hypothalamic-pituitary-thyroid (HPT) axis. These findings provide further evidence that C-terminal peptide derivatives of classical hormones possess intrinsic biological activities.