A non-classical ISRE/ISGF3 pathway mediates induction of RANTES gene transcription by type I IFNs.

RANTES (regulated upon activation normal T cell expressed and secreted) is a chemoattractant cytokine important in the generation of inflammatory responses and human immunodeficiency virus resistance. In hematopoietic cells, RANTES is over-expressed by type I interferons (IFN-alpha and IFN-beta). The upstream region of the RANTES gene promoter contains a distal low affinity IFN-stimulated response element (ISRE). Specific mutagenesis in this ISRE-like motif abolished the activation of RANTES transcription by type I IFNs. Examination of the ISRE binding factors strongly suggested that signal transducer and activator of transcription (Stat)-2 and p48/IFN-stimulated gene factor 3gamma (ISGF3gamma) are not required for the induction of RANTES by type I IFNs. The specific requirement of Stat-1 was demonstrated using Stat-1-deficient U3A cells. These results revealed a non-classical ISRE/ISGF3 signal transduction pathway for the induction of RANTES by type I IFNs.