Identification of transforming growth factors actively transcribed during the progress of liver fibrosis in biliary atresia.

BACKGROUND/PURPOSE: Transforming growth factor-beta (TGF-beta) 1 and 2 and their receptors TbetaR-I, TbetaR-II, and TbetaR-III are powerful profibrogenic mediators in the body. Their expression has not been completely elucidated in the progress of liver fibrosis associated with biliary atresia (BA).

METHODS

The authors compared the cytokine expression in the liver of 3 patients with BA at Kasai's procedure (KP) and in 3 patients at liver transplantation (LT). Two liver samples from children with no liver disorders served as normal controls (CO). Real-time quantitative reverse transcriptase polymerase chain reaction (QRT-PCR) was used to confirm the findings of relative mRNA expression of TGF-beta1 and 2 and their receptors. An immunohistochemistry and an enzyme-linked immunoassay (ELISA) were used to localize the liver cells that express TGF-beta2 and to quantitate the protein expression among groups.

RESULTS

Compared with controls, both TGF-beta1 and TGF-beta2 mRNA expression increased in the liver during the progress of liver fibrosis in patients with KP and LT on the array. Only TGF-beta2 showed a significant increase in expression in LT compared with KP and CO (P =.001 for TGF-beta2 and P = 0.054 for TGF-beta1). Both TbetaR-I and TbetaR-II showed no significant change among groups; TbetaR-III decreased significantly in LT compared with CO (P =.011). TGF-beta2 immunostaining was mainly localized in the bile duct epithelium and was remarkably higher in LT in which the proliferating bile ductules and the hepatocytes contributed to the increase in immunostaining and possibly to significantly higher plasma TGF-beta2 protein levels in LT than in KP.

CONCLUSIONS

This study identified TGF-beta2 as the most actively transcribed TGF-beta gene during the progress of liver fibrosis in BA and found a reciprocal relationship of upregulation of TGF-beta2 with downregulation of TbetaR-III in LT.