Interferon-gamma (IFN-gamma) is known to be an antiproliferative, differentiating agent in many cell types, including neuroblastoma. In this study, we determined the effects of IFN-gamma on cellular growth and expression of insulin-like growth factor II (IGF-II) and IGF receptors in the human neuroblastoma cell line SH-SY5Y. Incubation of SH-SY5Y cells in IFN-gamma (20-100 U/ml) induced the formation of long neuritic processes. IFN-gamma treatment also induced decreases in [3H]TdR incorporation, as well as serum-dependent changes in cell number. Treatment with IFN-gamma reduced cell number 33% in the presence of serum but had no effect on cell number in the absence of serum. IGF-II mRNA content was 60% inhibited by IFN-gamma, and was not serum dependent. The concentration of immunoreactive IGF-II in SH-SY5Y conditioned medium was also reduced in the presence of IFN-gamma, to less than half of control levels. In contrast, type I IGF receptor mRNA content was increased more than three-fold after treatment with IFN-gamma and serum. Co-incubation in IFN-gamma (20-100 U/ml) and IGF-II (3-10 nM) prevented the inhibitory effects of IFN-gamma on [3H]TdR incorporation in serum-free media. Our results suggest that IFN-gamma may inhibit DNA synthesis and cell growth by interfering with an IGF-II/type I IGF receptor autocrine growth or survival mechanism.