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Submitted on October 12, 2005
Accepted on December 22, 2005
Thyroid Section, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston MA 02115; Tupper Research Institute and Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, New England Medical Center, 750 Washington St, Boston, MA 02111; Department of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary; Department of Medicine/Endocrinology, University of Colorado Health Sciences Center at Fitzsimons, Aurora, CO 80045; Division of Endocrinology, Children's Hospital Boston, Boston, MA 02115
* To whom correspondence should be addressed. E-mail: abianco{at}partners.org.
Thyroxine (T4), the main product of thyroid secretion, is a critical signal in plasma that mediates the TSH (TSH) negative feedback mechanism. As a prohormone, T4 must be converted to T3 to acquire biological activity; thus, type 2 iodothyronine deiodinase (D2) is expected to play a critical role in this feedback mechanism. However, the mechanistic details of this pathway are still missing because, counter-intuitively, D2 activity is rapidly lost in the presence of T4 by a ubiquitin-proteasomal mechanism. In the present study, we demonstrate that D2 and TSH are co-expressed in rat pituitary thyrotrophs and that hypothyroidism increases D2 expression in these cells. Studies using two murine-derived thyrotroph cells, TtT-97 and T
T1, demonstrate high expression of D2 in thyrotrophs and confirm its sensitivity to negative regulation by T4-induced proteasomal degradation of this enzyme. Despite this, expression of the Dio2 gene in TT1 cells is higher than their T4-induced D2 ubiquitinating capacity. As a result, D2 activity and net T3 production in these cells are sustained even at free T4 concentrations that are severalfold above the physiological range. In this system, free T4 concentrations and net D2-mediated T3 production correlated negatively with TSH
gene expression. These results resolve the apparent paradox between the homeostatic regulation of D2 and its role in mediating the critical mechanism by which T4 triggers the TSH negative feedback.
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