Atypical expression of type 2 iodothyronine deiodinase in thyrotrophs explains the thyroxine-mediated pituitary thyrotropin feedback mechanism.
T(4), the main product of thyroid secretion, is a critical signal in plasma that mediates the TSH-negative feedback mechanism. As a prohormone, T(4) must be converted to T(3) 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 T(4) 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 TalphaT1, demonstrate high expression of D2 in thyrotrophs and confirm its sensitivity to negative regulation by T(4)-induced proteasomal degradation of this enzyme. Despite this, expression of the Dio2 gene in TalphaT1 cells is higher than their T(4)-induced D2 ubiquitinating capacity. As a result, D2 activity and net T(3) production in these cells are sustained, even at free T(4) concentrations that are severalfold above the physiological range. In this system, free T(4) concentrations and net D2-mediated T(3) production correlated negatively with TSHbeta gene expression. These results resolve the apparent paradox between the homeostatic regulation of D2 and its role in mediating the critical mechanism by which T(4) triggers the TSH-negative feedback.
Christoffolete
Marcelo A
MA
Thyroid Section, Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Ribeiro
Rogério
R
Singru
Praful
P
Fekete
Csaba
C
da Silva
Wagner S
WS
Gordon
David F
DF
Huang
Stephen A
SA
Crescenzi
Alessandra
A
Harney
John W
JW
Ridgway
E Chester
EC
Larsen
P Reed
PR
Lechan
Ronald M
RM
Bianco
Antonio C
AC
D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007453:Iodide Peroxidase / Q000032:analysis / Q000235:genetics*; D008297:Male; D010902:Pituitary Gland / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013972:Thyrotropin / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D013974:Thyroxine / Q000502:physiology*; D014284:Triiodothyronine / Q000096:biosynthesis; D000097564:Iodothyronine Deiodinase Type II
D007453:Iodide Peroxidase; D013972:Thyrotropin; D013974:Thyroxine; D014284:Triiodothyronine; D000097564:Iodothyronine Deiodinase Type II