期刊
LABORATORY INVESTIGATION
卷 90, 期 5, 页码 674-684出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/labinvest.2010.48
关键词
hepatic stellate cells; liver fibrosis; p75 neurotrophin receptor; Rho activation; thyroid hormones
资金
- Israeli Ministry of Health
We have previously shown that hyperthyroidism is detrimental for liver fibrosis and in this study we have investigated the mechanisms regulating triiodothyronine (T3) and L-thyroxine (T4) activation of hepatic stellate cells (HSC). Expression of alpha-smooth muscle actin (alpha SMA) and p75 neurotrophin receptor (p75NTR) was determined by western blot analyses and transient transfection of the promoters. Rho activation was assayed using a pull-down assay and by ELISA. Expression of thyroid hormone receptor alpha 1 decreases, whereas T4 receptor integrin alpha V beta 3 increases, with transdifferentiation of HSC to myofibroblasts. T3 and T4 enhance HSC activation, without affecting proliferation or phosphorylation of mitogen-activated protein kinase, signal transducer and activator of transcription 3 or Akt. Addition of 10(-7) M T3 or T4 to thyroid hormone-depleted serum induces a twofold increase in activation marker alpha SMA, as well as upregulation of p75NTR protein levels. Both hormones enhance transcription of alpha SMA and p75NTR. We report a novel signaling pathway for thyroid hormones, activation of Rho. T4 induces activation of Rho acting through alpha v beta 3 integrin, and the activation is abolished by the T4 antagonist, tetraiodothyroacetic acid, by peptide RGD and by a function-blocking antibody to integrin beta 3. T3 and T4 increase phosphorylation of non-muscle myosin light chain II, a downstream signal to Rho/Rho-kinase activation. T3 also induces expression of tumor necrosis factor-alpha. In vivo, administration of T3 or T4 together with thioacetamide (TAA) enhances fibrosis after 3 weeks, compared with the TAA-treated group, accompanied by increased alpha SMA in T3- and T4-treated groups, and of p75NTR in T4-treated rats. Thyroid hormones enhance activation of HSC through increased p75NTR and alpha SMA expression and activation of Rho, therefore accelerating development of liver fibrosis. Laboratory Investigation (2010) 90, 674-684; doi:10.1038/labinvest.2010.48; published online 15 March 2010
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