Two Mechanisms of Cell Resistance to Repeated Stimulation of Interferon 1

Summary

Human fibroblasts treated with the synthetic interferon-stimulating polymer polyinosinate:polycytidylate (I:C) became resistant (or “tolerant”) to a subsequent stimulation of interferon by either I:C or Newcastle disease virus (NDV). Tolerance to I:C reached a maximum around the time of termination of the first interferon response. After this time the cells gradually recovered some sensitivity to a second stimulation of interferon by I:C. In contrast, tolerance to NDV persisted and increased after termination of the primary interferon response by I:C. Treatment of human fibroblasts with interferon inhibited the subsequent production of interferon by NDV but not by I:C. When human fibroblasts were pretreated with a moderate dose of actinomycin D, tolerance to I:C was not observed. Furthermore, tolerance to I:C was significantly diminished when cells were only briefly exposed to I:C, although high levels of interferon were produced by this treatment. A model is proposed by which cells develop resistance to repeated stimulation of interferon.