A REGULATORY DOMAIN WITHIN THE VIRUS-RESPONSE ELEMENT OF THE INTERFERON ALPHA-1 GENE ACTS AS A TRANSCRIPTIONAL REPRESSOR SEQUENCE AND DETERMINANT OF CELL-SPECIFIC GENE-EXPRESSION

Type-I interferons are encoded by a multigene family, the major member s of which are at least 13 IFN A subtypes and a single IFN B gene. IFN s A and B are induced in response to similar stimuli, such as virus in fection and double-stranded RNA, but in different cell types: the indu ction of IFN A is almost exclusively restricted to cells of lymphoid o rigin, while IFN B has been found to be induced in a variety of cell t ypes including fibroblasts. The virus-responsive enhancer element in t he promoter region of IFN A family members is largely responsible for the differential expression of individual subtypes in responsive cells . In this paper we describe experiments which address the issue of the differential expression of IFN A and IFN B in different cell types. W e show that IFN-beta is induced in a variety of cells of different ori gin, while not all of these are able to secrete IFN-alpha. By transfec tion of reporter gene constructs comprising the virus-responsive enhan cer from the IFN A1 and IFN B genes, we show that this differential re sponse is mediated at the level of transcription via these control ele ments. More detailed analysis of the function of these regions identif ies specific sequences within the IFN A1 virus response element that h as an inhibitory effect on expression in cells that are normally induc ible, and is also implicated in the overall suppression of IFN A induc tion in non-inducible cells.