In order to investigate the molecular basis of the regulation of interferon-inducible genes, we isolated the promoter region of two such genes coding for the (2'-S')oligo(adenylate) synthetase and a 56-kDa protein (IFI-56K). The regions surrounding the cap site were sequenced and compared with the sequences of vertebrate and viral DNA present in the Genbank data bank. Small DNA segments were found in both genes which are homologous to part of the promoter region of other genes, such as those of interferon-p, tumor necrosis factor / 3, interleukin-2 and its receptor. Since these homologies were found located in functionally important regions of these genes, we tested whether their inducers also enhance the (2'-5')oligo(adenylate) synthetase and IFI-56K gene expression. We found that poly(r1) . poly(rC) and interleukin-1, activators of the interferon-p gene and of T lymphocytes respectively, are both able to enhance IFI-56K mRNA accumulation in all cell lines tested.Cycloheximide even superinduces this gene when added together with poly(r1) . poly(rC) and interleukin-1 (but not when added with interferon). We showed that these inductions are direct and not mediated by interferon produced by cells in response to poly(r1) . poly(rC) or interleukin-1 . The promoter sequence analyses have thus led to the discovery of unexpected inducers, i.e. an interferon inducer such as poly(r1) . poly(rC) is also able to directly induce a gene that is under the control of interferon.Interferons are proteins or glycoproteins secreted by various cells in response to viral infection or other stimuli. They are defined by their antiviral activity, i.e. protection against subsequent infection by different viruses of pretreated, metabolically active cells. Beside the establishment of an antiviral state, interaction between interferon and its receptor on the cell surface also leads to a wide range of biological effects, such as the inhibition of cell growth and modulations of the immune system (for reviews see [l, 21. In that way interferons, as other cytokines, act as pleiotropic effectors, since they modify not only the biochemistry of some target cells but also the physiology of the entire organism. Conversely it has been suggested that some other cytokines (tumor necrosis factors c( and p [3,41) have intrinsic antiviral activities.Numerous cDNAs corresponding to interferon-inducible genes have been cloned but the biological function of these genes has been discovered in a few cases only. Their transcriptional regulation appears to be rather complex. Indeed, all the genes studied so far seem to behave differently with respect to their kinetics of mRNA accumulation after interferon treatment. Moreover, for a given gene, the response to interferon treatment is dependent on the type of interferon and target cell used [5 -111. Finally, amongst these genes, only some remain inducible in interferon-resistant lymphoblastoid (Daudi) cells, demonstrating the existence of at least two different pathways of induction downstream from the interacti...

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