Cross-linked cytokeratin polypeptides in liver and hepatoma cells: possible association with the process of cell degeneration and death.

We investigated transglutaminase-induced cross-linking of cytokeratin polypeptides in liver and hepatoma cells. To overcome the difficulties in the biochemical analysis of highly cross-linked polymers and aggregates of cytokeratins, cross-linked cytokeratin dimers were analyzed by immunoblotting to evaluate the degree of cross-linking of cytokeratins. Covalently cross-linked cytokeratin dimers were not detectable in normal rat liver cells. However, cytokeratin dimers and high-molecular-weight cytokeratin polymers were detected in liver tissue with histological evidence of coagulative necrosis induced by ischemia or carbon tetrachloride. Treatment of cultured hepatoma cells with the Ca2+ ionophore A23187 showed a dose-dependent, time-dependent decrease of cell viability. The appearance of cytokeratin dimers was shown to be correlated with cell death. These results suggest that the transglutaminase-induced cross-linking of cytokeratin polypeptides in liver and hepatoma cells is closely associated with the process of cell degeneration and death.