Proliferation of hepatic lineage cells of normal C57BL and interleukin-6 knockout mice after cocaine-induced periportal injury.

The cellular response to periportal liver injury, induced by phenobarbital feeding and cocaine injection, is used to compare the restitutive proliferation of hepatocytes, cholangiocytes, and oval cells in the livers of normal control to those of interleukin-6 (IL-6) knockout mice. After this injury hepatocytes in noninjured middle and central zones start to proliferate first, followed by proliferation of cholangiocytes and intraportal oval cells. Proliferation of all cell types peaks at 2 days, but oval cells continue to proliferate and differentiate through days 4 and 6 as they reconstitute the necrotic zone. By day 10, the injured zone is completely repaired, and no dividing cells remain. During the first 3 to 4 days after injury, the number of proliferating hepatocytes, cholangiocytes, and sinusoidal cells is lower in IL-6 knockout mice than in normal mice, whereas the number of dividing oval cells is higher. However, overall repair of the injury is accomplished in the same time period in both groups. During repair of the periportal zone, oval cells acquire differentiation markers of hepatocytes as they cross the zone of injury. In conclusion, the phenobarbital/cocaine injury model is useful to study restitutive proliferation of mouse liver cell lineages. The proliferative response in IL-6 knockout mice shows that IL-6 is not required for proliferation of liver cells; timely repair of liver injury occurs in both normal and IL-6 knockout mice. Increased proliferation of oval cells in IL-6 knockout mice may compensate for the lower proliferation of other liver cell types.