Thyroid hormone inhibits biliary growth in bile duct-ligated rats by PLC/IP sub(3)/Ca super(2+)-dependent downregulation of SRC/ERK1/2
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 alpha sub(1)-, alpha sub(2)-, beta sub(1)-, and...
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Veröffentlicht in: | American Journal of Physiology: Cell Physiology 2007-04, Vol.292 (4), p.C1467-C1475 |
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Zusammenfassung: | 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 alpha sub(1)-, alpha sub(2)-, beta sub(1)-, and beta sub(2)-thyroid hormone receptors (THRs) by immunohistochemistry in liver sections from normal and BDL rats. BDL rats were treated with T3 (38.4 mu g/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 mu M) in the absence/presence of U-73122 (PLC inhibitor) or BAPTA/AM (intracellular Ca super(2+) chelator) before measurement of PCNA protein expression by immunoblots. The in vitro effects of T3 (1 mu M) on 1) cAMP, IP sub(3), and Ca super(2+) levels and 2) the phosphorylation of Src Tyr139 and Tyr530 (that, together, regulate Src activity) and ERK1/2 of BDL cholangiocytes were also evaluated. alpha sub(1)-, alpha sub(2)-, beta sub(1)-, and beta sub(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 1) increased IP sub(3) and Ca super(2+) levels and 2) decreased Src and ERK1/2 phosphorylation of BDL cholangiocytes. T3 inhibits cholangiocyte proliferation of BDL rats by PLC/IP sub(3)/Ca super(2+)-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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ISSN: | 0363-6143 1522-1563 |