AbstractA novel recombinant molecule, termed IL‐6c and consisting of a chimera of interleukin 6 (IL‐6) and its soluble receptor is extremely potent in stimulating proliferation of hematopoietic progenitors. We investigated the effect of the IL‐6c on the proliferation and differentiation of E14 fetal hepatocytes. IL‐6c, in a dose‐dependent manner, stimulated proliferation of E14 fetal rat hepatocytes. Adult hepatocyte mitogens together with IL‐6c showed no further effect on proliferation. Hematopoietic stem cells mitogens SCF and flt3 ligand (FL) were also mitogenic for fetal hepatocytes, but did not further enhance the effect of IL‐6c on cell proliferation. IL‐6c decreased expression of fetal markers α‐fetoprotein (AFP) and gamma‐glutamyltranspeptidase, and induced expression of adult enzyme glucose‐6‐phosphatase (Gluc‐6‐P) in E14 hepatocytes. On the other hand, IL‐6c strongly reduced, in a dose‐dependant manner, expression of albumin and tyrosine aminotransferase (TAT). However, when the cells were grown for 3 days with IL‐6c, and IL‐6c was removed for the next 5 days, expression of albumin and TAT returned to levels found in control cultures. In conclusion, IL‐6c stimulated proliferation and affected gene expression in fetal hepatocytes in culture. © 2004 Wiley‐Liss, Inc.