Thyroid hormone inhibits biliary growth in bile duct-ligated rats by PLC/IP3/Ca2+-dependent downregulation of SRC/ERK1/2
- 1 April 2007
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Cell Physiology
- Vol. 292 (4), C1467-C1475
- https://doi.org/10.1152/ajpcell.00575.2006
Abstract
The role of the thyroid hormone agonist 3,3′,5 l-tri-iodothyronine (T3) on cholangiocytes is unknown. We evaluated the in vivo and in vitro effects of T3 on cholangiocyte proliferation of bile duct-ligated (BDL) rats. We assessed the expression of α1-, α2-, β1-, and β2-thyroid hormone receptors (THRs) by immunohistochemistry in liver sections from normal and BDL rats. BDL rats were treated with T3 (38.4 μg/day) or vehicle for 1 wk. We evaluated 1) biliary mass and apoptosis in liver sections and 2) proliferation in cholangiocytes. Serum-free T3 levels were measured by chemiluminescence. Purified BDL cholangiocytes were treated with 0.2% BSA or T3 (1 μM) in the absence/presence of U-73122 (PLC inhibitor) or BAPTA/AM (intracellular Ca2+chelator) before measurement of PCNA protein expression by immunoblots. The in vitro effects of T3 (1 μM) on 1) cAMP, IP3, and Ca2+levels and 2) the phosphorylation of Src Tyr139 and Tyr530 (that, together, regulate Src activity) and ERK1/2 of BDL cholangiocytes were also evaluated. α1-, α2-, β1-, and β2-THRs were expressed by bile ducts of normal and BDL rats. In vivo, T3 decreased cholangiocyte proliferation of BDL rats. In vitro, T3 inhibition of PCNA protein expression was blocked by U-73122 and BAPTA/AM. Furthermore, T3 1) increased IP3and Ca2+levels and 2) decreased Src and ERK1/2 phosphorylation of BDL cholangiocytes. T3 inhibits cholangiocyte proliferation of BDL rats by PLC/IP3/Ca2+-dependent decreased phosphorylation of Src/ERK1/2. Activation of the intracellular signals triggered by T3 may modulate the excess of cholangiocyte proliferation in liver diseases.Keywords
This publication has 50 references indexed in Scilit:
- Thyroid Hormone Stimulates Protein Synthesis in the Cardiomyocyte by Activating the Akt-mTOR and p70S6K PathwaysJournal of Biological Chemistry, 2006
- Influence of thyroid hormone receptors on breast cancer cell proliferationAnnals Of Oncology, 2005
- cAMP stimulates the secretory and proliferative capacity of the rat intrahepatic biliary epithelium through changes in the PKA/Src/MEK/ERK1/2 pathwayJournal of Hepatology, 2004
- Hyper and hypothyroidism change the expression and diurnal variation of thyroid hormone receptor isoforms in rat liver without major changes in their zonal distributionMolecular and Cellular Endocrinology, 2004
- Downregulation of Vascular Angiotensin II Type 1 Receptor by Thyroid HormoneHypertension, 2003
- Gastrin inhibits cholangiocarcinoma growth through increased apoptosis by activation of Ca2+-dependent protein kinase C-αJournal of Hepatology, 2001
- Endocrinology of Growth and Growth FactorsConnective Tissue Research, 1995
- Hepatocyte proliferation and gene expression induced by triiodothyroninein vivo andin vitroHepatology, 1994
- Liver changes in patients with hyperthyroidismLiver International, 1991
- Biliary physiology in rats with bile ductular cell hyperplasia. Evidence for a secretory function of proliferated bile ductules.JCI Insight, 1988