TGF-β1 and TGF-β2 abundance in liver diseases of mice and men

TGF-beta 1 is a major player in chronic liver diseases promoting fibrogenesis and tumorigenesis through various mechanisms. The expression and function of TGF-beta 2 have not been investigated thoroughly in liver disease to date. In this paper, we provide evidence that TGF-beta 2 expression correlates with fibrogenesis and liver cancer development. Using quantitative realtime PCR and ELISA, we show that TGF-beta 2 mRNA expression and secretion increased in murine HSCs and hepatocytes over time in culture and were found in the human-derived HSC cell line LX-2. TGF-beta 2 stimulation of the LX-2 cells led to upregulation of the TGF-beta receptors 1, 2, and 3, whereas TGF-beta 1 treatment did not alter or decrease their expression. In liver regeneration and fibrosis upon CCl4 challenge, the transient increase of TGF-beta 2 expression was accompanied by TGF-beta 1 and collagen expression. In bile duct ligation-induced fibrosis, TGF-beta 2 upregulation correlated with fibrotic markers and was more prominent than TGF-beta 1 expression. Accordingly, MDR2-KO mice showed significant TGF-beta 2 upregulation within 3 to 15 months but minor TGF-beta 1 expression changes. In 5 of 8 hepatocellular carcinoma (HCC)/hepatoblastoma cell lines, relatively high TGF-beta 2 expression and secretion were observed, with some cell lines even secreting more TGF-beta 2 than TGF-beta 1. TGF-beta 2 was also upregulated in tumors of TGF alpha/cMyc and DEN-treated mice. The analysis of publically available microarray data of 13 human HCC collectives revealed considerable upregulation of TGF-beta 2 as compared to normal liver. Our study demonstrates upregulation of TGF-beta 2 in liver disease and suggests TGF-beta 2 as a promising therapeutic target for tackling fibrosis and HCC.