THE ROLE OF STAT AND C EBP TRANSCRIPTION FACTORS IN THE SYNERGISTIC ACTIVATION OF RAT SERINE-PROTEASE INHIBITOR-3 GENE BY INTERLEUKIN-6 ANDDEXAMETHASONE/

The rat serine proteinase inhibitor 3 gene is activated by interleukin 6 (IL-6) and glucocorticoids in hepatic cells. We report here that a 147 bp promoter is sufficient for both IL-6 stimulation and glucocorti coid enhancement of IL-6 induced transcription. Within this region we identified two functional elements binding transcription factors from the C/EBP (CCAAT/enhancer binding proteins) and Stat (signal transduce rs and activators of transcription) families. Mutations introduced int o the Stat binding site resulted in a loss of responsiveness, showing that this element is indispensable for activation. In contrast, the pr omoter containing the mutated C/EBP binding site was still responsive to IL-6 and glucocorticoids; however, the magnitude of the induction w as decreased by 50%. The Stat binding element is an enhancer capable o f conferring both responsiveness to IL-6 and partial enhancement of gl ucocorticoids on to a heterologous promoter, In response to IL-6 this element rapidly binds acute-phase response factor (APRF/ Stat3) and, l ater, the protein(s) that require ongoing protein synthesis and is rec ognized by anti-Stat3 antibodies. In addition, long-term treatment wit h IL-6 results in sustained phosphorylation of APRF/Stat3.