ACTIVATION OF THE RAT SERINE PROTEINASE-INHIBITOR-3 GENE BY INTERFERON-GAMMA VIA THE INTERLEUKIN-6-RESPONSIVE ELEMENT

Transcription of rat serine proteinase inhibitor 3 (SPI-3) gene is rap idly induced in the liver in response to inflammation. Treatment of ra t hepatoma H-35 cells with interferon gamma (INF gamma) results in the immediate induction of this gene, with its 147 bp-long promoter being sufficient for activation. Within this promoter we have identified an IFN gamma-responsive element which maps to the signal transducer and activator of transcription (Stat)3-binding site. Mutation of this elem ent causes a loss of responsiveness to IFN gamma, whereas fusion to a heterologous promoter confers a positive response on IFN gamma. The la tter apparently induces the binding of a protein, identified as Stat1, to the described element, which gradually decreases within 24 h. Thus the induction of the SPI-3 gene by IFN gamma correlates with the bind ing of Stat1 to a specific element which, in turn, binds Stat3 in resp onse to interleukin 6.