The earlier discussion of the mechanism of action of T3 concerns the expression of genes which are under positive control of thyroid hormone. However, a roughly equal number of genes are negatively regulated by T3, in particular those involved in the negative feedback regulation of the hypothalamus– pituitary– thyroid axis (i.e. the TSHβ and the TRH genes). In the promoter regions of these genes negative TREs have been identified that often consist of only one half- site. In the TSHβ gene such a negative TRE has been found in close proximity to the AP- 1 site which mediates the stimulation of TSHβ gene transcription by TRH. As just mentioned, there appears to be a specific role for TRβ2 in the regulation of the negative TREs in the TSHβ and TRH genes. In contrast to gene regulation through positive TREs, binding of TRβ2 to negative TREs in the absence of T3 probably results in the activation of gene transcription. In the presence of T3, transcription is inhibited. The exact mechanism of this negative regulation of gene expression by T3 and any T3 receptor is still unclear.
TSHβ gene transcription is also strongly inhibited by 9- cis- retinoic acid, and this effect is mediated by the pituitary- specific RXRγ1 subtype, and involves both TRE- dependent and TRE- independent interactions with the TSHβ gene promoter. The clinical relevance of this effect is underscored by a recent study showing that treatment of patients with T- cell lymphoma with bexarotene, another RXR- selective ligand, induces central hypothyroidism. It is also interesting to mention that the TRH gene promoter contains a glucocorticoid response element. Hypothalamic TRH- producing cells also express the glucocorticoid receptor, and the interaction of this receptor with its response element appears to mediate the inhibition of TRH synthesis by glucocorticoids.
In addition to the regulation of TSHβ and α- subunit gene expression, T3 also acutely inhibits TSH secretion, the exact mechanism of which is still unresolved. Although T3 is the active hormone exerting the inhibition of TSH production and secretion, serum T4 appears to be a major player in the negative feedback regulation of the hypothalamus– pituitary– thyroid axis by acting as a precursor for local D2- mediated generation of T3 at these central sites.
Recent research in two particular areas has led to important advances in our understanding of the mechanism of action of T3. One type of study has utilized T3 receptor knockout and mutant mice in which one or more of the different T3 receptor isoforms is deleted or mutated. These studies reveal which organ functions critically depend on the type of T3 receptors they express. Similarly, mice mutant for NCoR or SMRT have revealed important insights in the function of corepressors in thyroid hormone signalling. Much knowledge regarding the molecular mechanisms of T3 receptor/ T3 action has also been gained from studies in patients with thyroid hormone resistance associated with mutations in TRβ (resistance to thyroid hormone; RTH). In recent years, patients with mutations in TRα have been identified.
