The human neuroendocrine thyrotropin-releasing hormone receptor promoter is activated by the haematopoietic transcription factor c-Myb

Abstract

Thyrotropin-releasing hormone (TRH) receptor (TRHR) is a G-protein-coupled receptor playing a crucial role in the anterior pituitary where it controls the synthesis and secretion of thyroidstimulating hormone and prolactin. Its widespread presence not only in the central nervous system, but also in peripheral tissues, including thymus, indicates other important, but unknown, functions. One hypothesis is that the neuropeptide TRH could play a role in the immune system. We report here that the human TRHR promoter contains 11 putative response elements for the haematopoietic transcription factor c-Myb and is highly Mybresponsive in transfection assays. Analysis of Myb binding to putative response elements revealed one preferred binding site in intron 1 of the receptor gene. Transfection studies of promoter deletions confirmed that this high-affinity element is necessary for efficient Myb-dependent transactivation of reporter plasmids in CV-1 cells. The Myb-dependent activation of the TRHR promoter was strongly suppressed by expression of a dominant negative Myb-Engrailed fusion. In line with these observations, reverse transcriptase PCR analysis of rat tissues showed that the TRHR gene is expressed both in thymocytes and bone marrow. Furthermore, specific, high-affinity TRH agonist binding to cell-surface receptors was demonstrated in thymocytes and a haematopoietic cell line. Our findings imply a novel functional link between the neuroendocrine and the immune systems at the level of promoter regulation.

Hypothalamic neurohormones and immune responses

“…Thymus expression of the TRHR has been reported by several authors (Fukusumi et al, 1995; Mellado et al, 1999; Montagne et al, 1999; Matre et al, 2003). …”

“…TRH, the smallest known peptide hypophyseotropic hormone, is a tripeptide (pGlu-His-Pro-NH 2 ; where pGlu stands for pyroglutamic acid) that is released from the hypothalamus and transported via the portal vascular system to the anterior pituitary where it stimulates the release of thyroid-stimulating hormone (TSH) and prolactin from the anterior pituitary (Matre et al, 2003). …”

“…TRH has been found as part of immune system tissues and blood elements (Matre et al, 2003). This topic will be discussed in depth in the following sections.…”

“…Expression analysis in rat demonstrated the presence of TRHR mRNA in bone marrow (Montagne et al, 1999; Matre et al, 2003) and in the rat natural-killer cell line RNK-16 (Matre et al, 2003). This expression was shown to be functional as evidenced by TRH binding to surface receptors on thymocytes and RNK-16 cells.…”

Hormonal control of T-cell development in health and disease

“…87 Additionally, TRH, which encodes prothyrotropin-releasing hormone, is also transcribed in the thymus of the rat. 88 Given the local production of prothyrotropin-releasing hormone, the intrathymic expression of the thyrotropin receptor and the fact that this neuropeptide is able to enhance thymocyte proliferation, 89,90 an autocrine/paracrine circuit mediated by thyrotropin receptor might control the thymus physiology. However, whether a complete thyrotropin-releasing hormone-TSH-T 3 /T 4 cascade occurs in the thymus remains to be defined.…”