Ezquerro Ignacio-José, Lasarte Juan-José, Dotor Javier, Castilla-Cortázar Inma, Bustos Matilde, Peñuelas Iván, Blanco Gemma, Rodríguez Carlos, Lechuga Maria del Carmen G, Greenwel Patricia, Rojkind Marcos, Prieto Jesús, Borrás-Cuesta Francisco
Departamento de Medicina Interna, Universidad de Navarra, Pamplona, Spain.
Cytokine. 2003 Apr;22(1-2):12-20. doi: 10.1016/s1043-4666(03)00101-7.
Transforming growth factor beta1 (TGF-beta1) is a pleiotropic cytokine, which displays potent profibrogenic effects and is highly expressed in fibrotic livers. For this reason, development of TGF-B1 inhibitors might be of great importance to control liver fibrogenesis as well as other undesired side effects due to this cytokine. Potential peptide inhibitors of TGF-beta1 (derived from TGF-beta1 and from its type III receptor) were tested in vitro and in vivo using different assays. Peptides P11 and P12, derived from TGF-beta1, and P54 and P144, derived from its type III receptor, prevented TGF-beta1-dependent inhibition of MV1Lu proliferation in vitro and markedly reduced binding of TGF-beta1 to its receptors. P144 blocked TGF-beta1-dependent stimulation of a reporter gene under the control of human alpha2(I) collagen promoter. Intraperitoneal administration of P144 also showed potent antifibrogenic activity in vivo in the liver of rats receiving CCl4. These rats also showed a significant decrease in the number of activated hepatic stellate cells as compared with those treated with saline only. These results suggest that short synthetic peptides derived from TGF-beta1 type III receptor may be of value in reducing liver fibrosis in chronic liver injury.
转化生长因子β1（TGF-β1）是一种多效性细胞因子，具有强大的促纤维化作用，在纤维化肝脏中高度表达。因此，开发TGF-β1抑制剂对于控制肝纤维化以及该细胞因子引起的其他不良副作用可能非常重要。使用不同的试验在体外和体内对TGF-β1的潜在肽抑制剂（源自TGF-β1及其III型受体）进行了测试。源自TGF-β1的肽P11和P12以及源自其III型受体的P54和P144在体外可防止TGF-β1依赖性对MV1Lu增殖的抑制，并显著降低TGF-β1与其受体的结合。P144阻断了在人α2（I）胶原启动子控制下的报告基因的TGF-β1依赖性刺激。腹腔注射P144在接受四氯化碳的大鼠肝脏中也显示出体内强大的抗纤维化活性。与仅用盐水处理的大鼠相比，这些大鼠活化的肝星状细胞数量也显著减少。这些结果表明，源自TGF-β1 III型受体的短合成肽在减少慢性肝损伤中的肝纤维化方面可能具有价值。
