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1 Department of Gastroenterology, Polytechnic University of Marche, Ancona, Italy, Ancons, Marche, Italy
2 Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
3 Division of Research and Education, Scott and White Memorial Hospital, Temple, Texas, United States
4 Div. R&E, Scott & White Hospital, Temple, Texas, United States
5 R&E, Scott & White Hospital, Temple, Texas, United States
6 Gastroenterology, Polytechnic University of Marche, Ancona, Italy, Ancons, Marche, Italy; Gastroenterology, University of Rome, Roma, Lazio, Italy
7 Medicine, The Texas A&M University System Health Science Center, College of Medicine, Temple, Texas, United States
8 Research, Central Texas Veterans Health Care System and The Texas A & M University System Health Science Center College of Medicine, Temple, Texas, United States
9 Internal Medicine and Medical Physiology, Central Texas Veterans Health Care System and The Texas A & M University System Health Science Center College of Medicine, Temple, Texas, United States
* To whom correspondence should be addressed. E-mail: galpini{at}tamu.edu.
The role of the thyroid hormone agonist 3,3',5 L-tri-iodothyronine (T3) on cholangiocytes are 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 
1, 2, 
1 and 2 thyroid hormone receptors (THRs) by immunohistochemistry in liver sections from normal and BDL rats. BDL rats were treated with T3 (38.4 micrograms/day) or vehicle for 1 week. We evaluated: (i) biliary mass and apoptosis in liver sections; and (ii) proliferation in cholangiocytes. Serum free-T3 levels were measured by chemiluminescence. Purified BDL cholangiocytes were treated with 0.2% BSA or T3 (1 micromolar) in the absence/presence of U-73122 (PLC inhibitor) or BAPTA/AM (intracellular Ca2+ chelator) before measuring PCNA protein expression by immunoblots. The in vitro effects of T3 (1 micromolar) on: (i) cAMP, IP3 and Ca2+ levels; and (ii) the phosphorylation of Src Tyr139 and Tyr530 (that, together, regulate Src activity) and ERK1/2 of BDL cholangiocytes were evaluated. 1, 2, 1 and 2 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: (i) increased IP3 and Ca2+ levels; and (ii) 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.
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