Contribution of transforming growth factor-a to thr development of hepatic fibrosis in alcoholic liver diseases

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Although it is well known that hepatic fibrosis develops in alcoholic liver diseases (ALD) without accompanying inflammation, the underlying mechanism is unclear. Using ethanol-exposed human HepG2 hepatoblastoma cells as a model for ALD, we previously found that ethanol exposure causes HepG2 cells to secrete a polypeptide factor which stimulates collagen synthesis in human IMR-90 fibroblasis. The aim of this study was to characterize and identify this factor.Collagen stimulating activity in conditioned media (CM) from ethanol-exposed HepG2 cells was assessed by its ability to stimulate synthesis of type I procollagen peptide (PIC) in IMR-90 cells. The identity of the factor was tested by the ability of antibodies to various cytokines to deplete collagen stimulating activity from CM.Transforming growth factor (TGF)-alpha in the CM of ethanol-treated HepG2 and serum TGF-alpha levels in patients with ALD were determined using an enzyme-linked immunosorbent assay. The collagen stimulating activity in CM could be depleted by antibody to TGF-alpha. Consistent with this, TGF-alpha in the CM of ethanol-treated HepG2 increased in a time-and dose-dependent manner. Suggesting that TGF-alpha may play a role in ALD, serum TGF-alpha levels in patients with ALD liver fibrosis were significantly higher than in patients with chronic viral hepatitis and viral cirrhosis. In conclusion, TGF-alpha may contribute to the development of hepatic fibrosis in ALD.