Identification of Transforming Growth Factors Actively Transcribed during the Progress of Liver Fibrosis in Biliary Atresia

Background/Purpose: Transforming growth factor-beta (TGF-β) 1 and 2 and their receptors TβR-I, TβR-II, and TβR-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-β1 and 2 and their receptors. An immunohistochemistry and an enzyme-linked immunoassay (ELISA) were used to localize the liver cells that express TGF-β2 and to quantitate the protein expression among groups. Results: Compared with controls, both TGF-β1 and TGF-β2 mRNA expression increased in the liver during the progress of liver fibrosis in patients with KP and LT on the array. Only TGF-β2 showed a significant increase in expression in LT compared with KP and CO (P = .001 for TGF-β2 and P = 0.054 for TGF-β1.) Both TβR-I and TβR-II showed no significant change among groups, TβR-III decreased significantly in LT compared with CO (P = .011). TGF-β2 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-β2 protein levels in LT than in KP. Conclusions: This study identified TGF-β2 as the most actively transcribed TGF-β gene during the progress of liver fibrosis in BA and found a reciprocal relationship of upregulation of TGF-β2 with downregulation of TβR-III in LT.