Intracellular accumulation of incompletely processed transforming growth factor-alpha polypeptides in ground glass hepatocytes of chronic hepatitis B virus infection

BACKGROUND: Transforming growth factor-alpha is an intracellularly processed and secreted polypeptide that induces a proliferative response in epithelial target cells and represents a potential regulatory factor in embryonic development, liver regeneration, and also hepatocarcinogenesis. We have observed focal transforming growth factor-alpha expression in liver tissues with chronic hepatitis B virus infection. METHODS: To further elucidate the nature of this focal transforming growth factor-alpha accumulation we have analyzed overall 23 different liver tissues with chronic hepatitis B virus and hepatitis C virus infection as well as normal liver tissues by immunohistology, ELISA, and Western immunoblot with and without immunoprecipitation. RESULTS: By immunohistology transforming growth factor-alpha polypeptides showed focal subcellular accumulation in ground glass hepatocytes, the histological hallmark of chronic hepatitis B virus infection, in co-localization with HBV-preS1 antigen. By ELISA and Western immunoblot increased tissue concentrations of transforming growth factor-alpha were demonstrated in chronically hepatitis B virus-infected liver tissues with ground glass hepatocytes, especially a 15-kD polypeptide, most likely representing an incompletely processed transforming growth factor-alpha polypeptide. Transforming growth factor-alpha retention in ground glass hepatocytes is not a general unspecific effect, since it was not observed for several other secretory liver proteins. Accumulated transforming growth factor-alpha in ground glass hepatocytes does not co-localize with Epidermal Growth Factor Receptor expression. CONCLUSION: Thus evidence is presented that a principally secreted (viral) polypeptide (HBV-preS1) can interfere with the secretion and processing of a second (cellular) protein (transforming growth factor-alpha). Accumulation of transforming growth factor-alpha may result from alteration of the endoplasmic reticulum due to storage of hepatitis B virus surface antigen particles. No evidence was found for transforming growth factor-alpha in ground glass hepatocytes to intracellularly interact with the Epidermal Growth Factor Receptor.