THE INTERLEUKIN-6-ACTIVATED ACUTE-PHASE RESPONSE FACTOR IS ANTIGENICALLY AND FUNCTIONALLY RELATED TO MEMBERS OF THE SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT) FAMILY

Interleukin-6 (IL-6), leukemia inhibitory factor, oncostatin M, IL-11, and ciliary neurotropic factor are a family of cytokines and neuronal differentiation factors which bind to composite plasma membrane recep tors sharing the signal transducing subunit gp130. We have shown recen tly that IL-6 and leukemia inhibitory factor rapidly activate a latent cytoplasmic transcription factor, acute-phase response factor (APRF), by tyrosine phosphorylation, which then binds to IL-6 response elemen ts of various IL-6 target genes. Here we demonstrate that APRF is acti vated by all cytokines acting through gp130 and is detected in a wide variety of cell types, indicating a central role of this transcription factor in gp130-mediated signaling. APRF activation is also observed in vitro upon addition of IL-6 to cell homogenates. Protein tyrosine k inase inhibitors block both the tyrosine phosphorylation and DNA bindi ng of APRF. The factor was purified to homogeneity from rat liver and shown to consist of a single 87-kDa polypeptide, while two forms (89 a nd 87 kDa) are isolated from human hepatoma cells. As reported earlier , the binding sequence specificity of APRF is shared by gamma interfer on (IFN-gamma) activation factor, which is formed by the Stat91 protei n. Partial amino acid sequence obtained from purified rat APRF demonst rated that it is likely to be related to Stat91. In fact, an antiserum raised against the amino-terminal portion of Stat91 cross-reacted wit h APRF, suggesting the relatedness of APRF and Stat91. Altogether, the se data indicate that APRF belongs to a growing family of Stat-related proteins and that IFN-gamma and IL-6 use similar signaling pathways t o activate IFN-gamma activation factor and APRF, respectively.