Liver hematopoietic progenitor cells (LHPC) and liver epithelial progenitor cells (LEPC) share a remarkable number of growth and differentiation-controlling receptor-ligand signaling systems. These likely account for the ability of the liver to support hematopoiesis in fetal life, and possibly for suggestions that LHPC can differentiate into hepatocytes. In these experiments, the kinetics and magnitude of LHPC and LEPC activation and expansion were studied by using a concanavalin A (Con A) liver injury model followed by partial hepatectomy (PH). Studies were performed in interleukin 6-deficient (IL-6(-/-)) mice and wild-type (IL-6(+/+)) controls, which show equal susceptibility to Con A- induced injury, because IL-6/gp130 signaling has been implicated in both LHPC and LEPC expansion. Con A pretreatment primed LHPC and LEPC for a rapid and parallel expansion after PH in IL-6(+/+) mice, which was significantly blunted and delayed in the IL-6(-/-) mice. Exogenous IL-6 given immediately before PH after Con A, augmented both LHPC and LEPC expansion in the IL-6(-/-) mice. Thus, the proinflammatory cytokine IL-6, commonly produced in liver injury and inflammatory disease, is an important growth factor involved in the expansion of LHPC and LEPC. This observation has implications for both hepatic carcinogenesis and transplantation.