THE SIGNALING PATHWAYS OF INTERLEUKIN-6 AND GAMMA-INTERFERON CONVERGEBY THE ACTIVATION OF DIFFERENT TRANSCRIPTION FACTORS WHICH BIND TO COMMON RESPONSIVE DNA ELEMENTS

Interleukin-6 (IL-6) and gamma interferon (IFN-gamma) induce a partial ly overlapping set of genes, including the genes for interferon regula tory factor 1 (IRF-1), intercellular adhesion molecule 1 (ICAM-1), and the acute-phase protein alpha(2)-macroglobulin. We report here that t he rat alpha(2)-macroglobulin promoter is activated by IFN-gamma in hu man hepatoma (HepG2) cells and that the IFN-gamma response element map s to the same site previously defined as the acute-phase response elem ent (APRE), which binds the IL-6-activated transcription factor APRF ( acute-phase response factor). As was reported for fibroblasts, the IFN -gamma-regulated transcription factor GAF is phosphorylated at tyrosin e after IFN-gamma treatment of HepG2 cells. IFN-gamma posttranslationa lly activates a protein which specifically binds to the alpha(2)-macro globulin APRE. This protein is shown to be identical or closely relate d to GAF. Although APRF and GAF are shown to represent different prote ins, their binding sequence specificities are very similar. APRF and G AF bind equally well to the APRE sequences of various acute-phase prot ein genes as well as to the IFN-gamma response elements of the IRF-1, ICAM-1, and other IFN-gamma-inducible genes. Transient transfection an alysis revealed that the IFN-gamma response elements of the IRF-1 and ICAM-1 promoters are able to confer responsiveness to both IFN-gamma a nd IL-6 onto a heterologous promoter. Therefore, APRF and GAF are like ly to be involved in the transcriptional induction of these immediate- early genes by IL-6 and IFN-gamma, respectively. Taken together, these results demonstrate that two functionally distinct hormones, IL-6 and IFN-gamma, act through common regulatory elements to which different transcription factors sharing almost the same sequence specificity bin d.