Date M, Matsuzaki K, Matsushita M, Sakitani K, Shibano K, Okajima A, Yamamoto C, Ogata N, Okumura T, Seki T, Kubota Y, Kan M, McKeehan W L, Inoue K
Third Department of Internal Medicine, Kansai Medical University, Osaka, Japan.
J Hepatol. 1998 Apr;28(4):572-81. doi: 10.1016/s0168-8278(98)80280-8.
BACKGROUND/AIMS: Transforming growth factor-beta (TGF-beta) is a family of multifunctional proteins that regulate hepatocyte proliferation, and biosynthesis of the extracellular matrix. In this study we examined whether modulation of TGF-beta receptor expression contributes to the liver diseases.
The mRNA expression of TGF-beta1, TGF-beta type I receptor (TGFbetaRI), TGF-beta type II receptor (TGFbetaRII) and TGF-beta type III receptor (TGFbetaRIII) in rat livers injured by CCl4 administration was studied by Northern blotting. The mRNA expression patterns were confirmed by in situ hybridization.
The peak of TGF-beta1 mRNA expression was observed 48 h after acute intoxication with CCl4 in nonparenchymal cells. However, the levels of TGFbetaRI and TGFbetaRII mRNA expression decreased from 24 h to 48 h and from 12 h to 48 h, respectively, and returned to the normal level by 72 h. TGFbetaRII mRNA expression was depressed more and for longer than that of TGFbetaRI mRNA. Analysis in separated hepatocytes and nonparenchymal cells from the injured livers indicated that the mRNA changes occurred in hepatocytes. Nonparenchymal cells expressed TGFbetaRI and TGFbetaRII mRNAs at constant levels during liver regeneration. TGFbetaRIII mRNA, which also decreased after 12 h, was not apparent in hepatocytes but only in nonparenchymal cells.
These observations suggest that: (i) whenever TGF-beta1 is increased in CCl4-treated livers, it may induce liver fibrogenesis via nonparenchymal cells; (ii) the mitoinhibitory effect of TGF-beta1 on hepatocytes is transiently relieved by down-regulation of TGF-beta receptors for 72 h post-damage; and (iii) the resistance to TGF-beta growth inhibition between 24 to 48 h may be predominantly due to down-regulation of the expression of TGFbetaRII.
背景/目的：转化生长因子-β（TGF-β）是一类多功能蛋白家族，可调节肝细胞增殖及细胞外基质的生物合成。在本研究中，我们检测了TGF-β受体表达的调节是否与肝脏疾病有关。
采用Northern印迹法研究四氯化碳（CCl4）诱导损伤的大鼠肝脏中TGF-β1、I型TGF-β受体（TGFβRI）、II型TGF-β受体（TGFβRII）和III型TGF-β受体（TGFβRIII）的mRNA表达。通过原位杂交证实mRNA表达模式。
在非实质细胞中，CCl4急性中毒后48小时观察到TGF-β1 mRNA表达达到峰值。然而，TGFβRI和TGFβRII mRNA表达水平分别在24小时至48小时以及12小时至48小时下降，并在72小时恢复至正常水平。TGFβRII mRNA表达的降低幅度更大且持续时间更长。对损伤肝脏分离的肝细胞和非实质细胞的分析表明，mRNA变化发生在肝细胞中。在肝脏再生过程中，非实质细胞中TGFβRI和TGFβRII mRNA表达水平保持恒定。TGFβRIII mRNA在12小时后也下降，在肝细胞中不明显，仅在非实质细胞中表达。
这些观察结果表明：（i）在CCl4处理的肝脏中，每当TGF-β1增加时，它可能通过非实质细胞诱导肝纤维化；（ii）损伤后72小时内，TGF-β受体的下调可短暂解除TGF-β1对肝细胞的有丝分裂抑制作用；（iii）24至48小时之间对TGF-β生长抑制的抗性可能主要归因于TGFβRII表达的下调。
