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Atypical Expression of Type 2 Iodothyronine Deiodinase in Thyrotrophs Explains the Thyroxine-Mediated Pituitary Thyrotropin Feedback Mechanism

Thyroid Section (M.A.C., R.R., W.S.d.S., J.W.H., P.R.L., A.C.B.), Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, and Division of Endocrinology (S.A.H., A.C.), Children’s Hospital Boston, Boston, Massachusetts 02115; Tupper Research Institute and Department of Medicine (P.S., C.F., R.M.L.), Division of Endocrinology, Diabetes, and Metabolism, New England Medical Center, Boston, Massachusetts 02111; Department of Endocrine Neurobiology (C.F.), Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Hungary; and Department of Medicine/Endocrinology (D.F.G., E.C.R.), University of Colorado Health Sciences Center at Fitzsimons, Aurora, Colorado 80045

Address all correspondence and requests for reprints to: Antonio C. Bianco, M.D., Ph.D., Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, HIM Building 643, Boston, Massachusetts 02115. E-mail: abianco{at}partners.org.

T₄, the main product of thyroid secretion, is a critical signal in plasma that mediates the 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, counterintuitively, 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 coexpressed in rat pituitary thyrotrophs and that hypothyroidism increases D2 expression in these cells. Studies using two murine-derived thyrotroph cells, TtT-97 and TT1, 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 TSHß 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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