Fetal rat hepatocytes incubated in the absence of hormonal signals, or under proliferative (presence of epidermal growth factor [EGF]) or differentiative (presence of dexamethasone) culture conditions, showed responsiveness to interleukin-6 (IL-6). Northern blotting analysis for some typical acute phase genes such as haptoglobin and other proteins not previously identified as acute-phase reactants, such as alpha-fetoprotein, beta 2-microglobulin, and fibronectin, showed a positive modulation by IL-6, in a dose-dependent manner. However, a well-characterized negative acute-phase reactant such as albumin was not responsive to IL-6. The well-established synergism between glucocorticoids and IL-6 on inducing transcription is absent in fetal hepatocytes. Conversely, the combination of IL-6 and EGF produced different patterns of expression, depending on the messenger RNA (mRNA) analyzed. Thus, EGF abolished the increased mRNA levels of haptoglobin caused by IL-6 but had no effect on other genes such as alpha-fetoprotein and fibronectin.